Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-Methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (100, 0.160 g, 0.55 mmol) in tetrahydrofuran (3.0 mL) was added tetra-n-butylammonium fluoride (0.145 g, 0.55 mmol). The reaction was stirred for 1 hour at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 3% methanol in dichloromethane to provide light yellow solid (101, 0.07 g, 95%). MS (ESI) [M+H+]+=133.2.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][S:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:16][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][S:5][CH2:4][CH:3]=[O:2]
Reactant: BrC(Br)(Br)Br
Reactant: COC(CSCCCCCCO)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=CCSCCCCCCBr

Procedure:
To a solution of 6-(2,2-dimethoxyethylthio)hexan-1-ol (example 101, step a) (1.85 g) in DCM (75 mL) at 0° C. under N2 was added carbon tetrabromide (3.31 g) followed by triphenylphosphine (2.62 g) portionwise. The resultant mixture was stirred at RT for 1.25 h then concentrated in vacuo. Purification was by silica gel chromatography eluting with 0-50% ethyl acetate in cyclohexane to give the subtitled compound as a yellow liquid. Yield 1.31 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH3:13]>>[Cl:1][C:2]1[N:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: N
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Product: Nc1ccc(C(F)(F)F)c(Cl)n1
Temperature: 93 °C
Yield: 46 %

Procedure:
2,6-Dichloro-3-(trifluoromethyl)pyridine (5.00 g, 23.2 mmol) and 28% aqueous ammonia (150 mL) were placed in a 250 mL autoclave. The mixture was heated at 93° C. for 21 h. The reaction was cooled to rt and extracted with EtOAc (100 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (2-20% EtOAc in petroleum ether as eluant) to give 6-chloro-5-(trifluoromethyl)pyridin-2-amine (2.1 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J=8.4 Hz, 1 H), 7.13 (br s, 2 H), 6.43 (d, J=8.4 Hz, 1 H). MS (ESI) m/z (M+H)+ 197.2
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([NH:21][CH3:22])[CH:13]=1.[OH-].[Na+]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=1[N:21]([CH3:22])[CH:8]=[O:10])(=[O:20])[CH3:19]
Reactant: O=CO
Reactant: CNc1cc(Cl)ccc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1ccc(Cl)cc1N(C)C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of acetic anhydride (12 ml) and formic acid (8 ml) was heated at 55° for 3 hours and then cooled to ambient temperature. 4'-Chloro-2'-(methylamino)acetophenone (9.7 g) was then added and the mixture stirred at ambient temperature overnight. Water (40 ml) was added and the mixture stirred in an ice/salt bath and neutralised by adding aqueous sodium hydroxide (specific gravity 1.5, 22 ml) whilst maintaining the temperature below 30°. The reaction mixture was extracted with dichloromethane (3×50 ml) and the combined extracts were dried over magnesium sulphate to give a solution of 2'-acetyl-5'-chloro-N-methylformanilide.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[C:5](=[O:20])[CH2:4][CH2:3]1.[OH-].[Na+]>O.CO>[O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[C:5](=[O:20])[CH2:4][CH2:3]1
Reactant: COC(=O)CCCN1C(=O)CCC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCN1C(=O)CCC(=O)c2ccccc21

Procedure:
Methyl 4-(2,5-dioxo-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)butanoate from step a (100 mg, 0.36 mmol) in water/methanol (0.7:2.0 ml) was treated with NaOH (1N, 0.80 ml) to obtain 63.0 mg of 4-(2,5-dioxo-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)butanoic acid.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[O:6][C:5]1=[O:13].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C>[N:14]1([CH2:2][CH2:3][N:4]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:7]3[O:6][C:5]2=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=c1oc2cccnc2n1CCBr
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=c1oc2cccnc2n1CCN1CCCCC1
Reaction time: 12 h

Procedure:
0.01 mol of 3-(2-bromoethyl)-3H-oxazolo[4,5-b]pyridin-2-one, dissolved in acetonitrile, 0.15 mol of piperidine and 0.015 mol of diisopropylethylamine are introduced into a round-bottomed flask placed under argon and surmounted by a condenser. The mixture is brought to 80° C. for 12 hours. It is cooled, the acetonitrile is evaporated off under vacuum and the residue is taken up with water. The alkalinity of the medium is checked and the medium is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated and the residue is recrystallized.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:22])=[CH:4][C:3]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)c(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccc1Br
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of 4-bromo-3-fluorotoluene (11.34 g, 60 mmol), azobisisobutyronitrile (0.99 g, 6 mmol), and N-bromosuccinimide (11.75 g, 66 mmol) in carbon tetrachloride (60 ml) was heated to reflux for 3.5 h. The reaction mixture was cooled to room temperature and then filtered through Celite, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Isco Combiflash, 40 g, ethyl acetate:hexane=0:100 to 100:0, gradient) to obtain the title compound (12.8 g, 80%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:6](=[O:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:10][CH:9]=1.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:6](=[O:26])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][CH2:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=1
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)Cc1ccc(SCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)Cc1ccc(SCc2ccccc2C(=O)O)cc1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
Methyl 2-{[(4-{2-[(2,4-difluorobenzyl)(heptyl)amino]-2-oxoethyl}phenyl)thio]methyl}-benzoate (31 mg, 0.057 mmol) was dissolved in THF (1 ml) and cooled in an ice-bath. Lithium hydroxide (2 mg, 0.075 mmol) in water (1 ml) was added. After the addition, the cooling bath was removed and the mixture was stirred overnight. LC-MS showed there was very little product. More lithium hydroxide (3 mg) was added and the mixture was stirred for 6 days more and HPLC showed about 30% product. More (3 mg) of lithium hydroxide was added and the mixture was stirred for 13 days more. It was evaporated in vacuum to remove THF. The residue was acidified with 10% hydrochloric acid, pH˜3, and extracted with ethyl acetate (×2). The organic phases were combined, dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 500 g/3 ml) using DCM, MeOH/DCM (0.5:99.5) as eluant gave 17 mg desired product, yield 56%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-])=O)[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].O1CCOCC1.[ClH:22]>CCO.[Pd]>[ClH:22].[NH2:13][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([OH:1])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COC(=O)c1cc(N)c(O)c(O)c1
Reaction time: 3 h
Yield: 98 %

Procedure:
To a stirred solution of methyl 3,4-dihydroxy-5-nitrobenzoate (11.9 g, 55.8 mmol) in EtOH (200 mL), 4M HCl in dioxane (13.96 mL, 55.8 mmol) and 10% palladium on carbon (4.0 g, 3.76 mmol) were added. The reaction mixture was hydrogenated at atmospheric pressure of H2 for 3 hours (TLC-monitoring). The resulting mixture was filtered and concentrated with the use of a rotary evaporator. The residue was triturated with ether (100 mL). The precipitate was filtered off and vacuum-dried to afford methyl 3-amino-4,5-dihydroxybenzoate hydrochloride (12.0 g, 54.6 mmol, 98% yield).
Reaction SMILES: I.C([O:6][C:7](=[O:46])[C@H:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:9][C:10](=[O:38])[C@H:11]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[NH:12][C:13](=[O:29])[CH2:14][C:15](=[O:28])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=1)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][NH:16][C:15]([CH2:14][C:13]([NH:12][C@H:11]([C:10]([NH:9][C@H:8]([C:7]([OH:46])=[O:6])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:38])[CH2:30][C:31](=[O:32])[OH:33])=[O:29])=[O:28])=[CH:20][CH:21]=1)(=[NH:26])[NH2:27]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)CC(=O)NCCc1ccc(C(=N)N)cc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: I
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(CCNC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1

Procedure:
100 mg of N-[N-[(p-amidinophenethyl-carbamoyl)acetyl]-3-(t-butoxycarbonyl)-L-alanyl]-3-phenyl-L-alanine t-butyl ester hydroiodide were reacted with trifluoroacetic acid as described in Example 1 to give 69 mg of N-[N-[(p-amidinophenethylcarbamoyl)acetyl]-L-α-aspartyl]-3-phenyl-L-alanine trifluoroacetate, m.p. 141°-143° C., after crystal-lisation using diethyl ether.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15](O)=[O:16])=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:29][C:30]1([NH2:34])[CH2:33][O:32][CH2:31]1>>[CH3:29][C:30]1([NH:34][C:15]([C:14]2[CH:18]=[CH:19][N:20]=[CH:21][C:13]=2[NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)=[O:11])=[O:16])[CH2:33][O:32][CH2:31]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Reactant: CC1(N)COC1
Product: CC1(NC(=O)c2ccncc2NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)COC1

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with 3-methyloxetan-3-amine, providing the title compound was obtained as yellow solid (44%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11]C=[CH:9][C:8]=2OC)[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].NC1N(C2CC[S:27]CC2)N=CC=1C#N>>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][S:27][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16]
Reactant: N#Cc1cnn(C2CCSCC2)c1N
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Product: NC(=O)c1cnn(C2CCSCC2)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-4-carbonitrile provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.67 (s, 1H), 4.09-3.97 (m, 1H), 2.89-2.82 (m, 2H), 2.72-2.68 (m, 2H), 2.15-2.10 (m, 4H). MS: (M+H m/z 227.1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[CH:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[C:5]=1[N+:9]([O-:11])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1c(O)cc(F)cc1F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(F)cc(F)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 72.7 %

Procedure:
To a solution of 4,6-difluoro-2-hydroxynitrobenzene (12.5 g, 71.1 mmol) in DMF (150 ml) was added sodium hydride (60% in oil, 3.70 g, 92.4 mmol) under stirring at 0° C., and the reaction mixture was stirred for 15 minutes. Benzyl bromide (11.0 ml, 92.4 mmol) was added dropwise at 0° C. After completion of the dropwise addition, the reaction mixture was stirred at 80° C. for 18 hours. After cooling to room temperature, the mixture was poured in ice-1N HCl to neutralize therewith, followed by extraction with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate/hexane (1/5) eluate fractions, 2-benzyloxy-4,6-difluoronitrobenzene (13.7 g, 73%) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[I:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[I:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(I)cc1
Yield: 67.7 %

Procedure:
0.75 g (0.00394 mol) of 1-benzyl-4-hydroxy-piperidine and 0.546 ml (0.00394 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 1.0 g (0.00375 mol) of 4-iodobenzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 1.07 g (68%) of 1-benzyl-piperidin-4-yl 4-iodo-benzoate were obtained as yellow crystals; m.p. 77°-78°.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[N:15]=[N:16][NH:17][N:18]=3)=[CH:12][N:11]=[C:10]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[CH:22][CH:21]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[CH2:35]([N:17]1[N:16]=[N:15][C:14]([C:13]2[C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:9][C:10]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[CH:22][CH:21]=3)=[N:11][CH:12]=2)=[N:18]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3nn[nH]n3)c(NC3CCCCC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3nnn(Cc4ccccc4)n3)c(NC3CCCCC3)n2)cc1

Procedure:
50 mg (0.1 mmol) (RS)—S-(4-{[4-(cyclohexylamino)-5-(2H-tetrazol-5-yl)-pyrimidine-2-yl]amino}phenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide, 18 mg (0.1 mmol) benzyl bromide, 71 mg (0.51 mmol) potassium carbonate and 17 mg (0.1 mmol) potassium iodide in 1.6 ml 2-butanone are stirred for 6 hours at 80° C. After cooling, the mixture is absorbed onto silica gel and purified chromatographically (DCM/EtOH 95:5). 43 mg (0.07 mmol; corresponding to 73% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:44]
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2N)c1N1CC[C@@H](F)[C@@H](N)CC1

Procedure:
Following the procedure for Example 221 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid gave, after purification via silica gel column chromatography (5-7% MeOH/DCM with 1% 7 N ammonia in MeOH), 296 as a cream solid (128 mg, 59% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.13-8.08 (m, 1H), 7.84 (s, 1H), 7.40-7.32 (m, 1H), 7.29-7.20 (m, 1H), 7.17 (dd, J=11.4, 8.3 Hz, 1H), 6.10 (s, 2H), 4.89 (dd, J=47.0, 7.0 Hz, 1H), 3.74 (s, 3H), 3.50-3.31 (m, 3H), 3.22-3.09 (m, 2H), 2.37-2.27 (m, 1H), 2.12-1.89 (m, 2H), 1.86-1.78 (m, 1H). Alkyl NH2 not seen. LCMS (ES+) m/z 448 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20]2)=[CH:11][CH2:10]1>CO.C(O)(=O)C.[Zn]>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20]2)=[CH:11][CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)[C@H]1CCCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H]([N+](=O)[O-])C2)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@H]1CCCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)C1
Yield: 91.2 %

Procedure:
To a solution of Example 17A (75 mg, 0.16 mmol) in a mixture of methanol/acetic acid (1.0 mL/1.0 mL), Zn powder (170 mg, 2.60 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (60 mg, 86%). MS (DCI) m/z 411 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:16]=[O:17])=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:18][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH:16]([OH:17])[CH3:18])=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(C)c1nc(-c2ccc(Br)cc2)oc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(Br)cc2)oc1C(C)O
Reaction time: 1 h
Yield: 40.8 %

Procedure:
A solution of 2-(4-bromo-phenyl)-4-isopropyl-oxazole-5-carbaldehyde (14.4 g, 84.9 mmol) in THF (300 mL) is cooled to −78° C. and treated dropwise with methyl magnesium bromide (25 mL, 75 mmol, 3M Et2O). After 1 h, more methyl magnesium bromide (12 mL, 36 mmol) is added. The reaction mixture is stirred 1.5 h, and saturated NH4Cl solution (10 ml) is added dropwise. The mixture is partitioned between saturated NH4Cl solution (10 ml), 1N HCl (25 mL), and Et2O (300 mL). The organic layer is washed with brine (150 mL), dried (Na2SO4), and concentrated. The crude product is purified by silica gel flash chromatography using hexanes:ethyl acetate (9:1 to 5:1) to give an offwhite solid (9.5 g, 63%).
Reaction SMILES: [C:1]([CH:3]([C:7]1[C:8]([CH2:24][CH:25]2[CH2:27][CH2:26]2)=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]([CH:17]([F:19])[F:18])=[N:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[CH2:4][CH:5]=[CH2:6])#N.[H-].C([Al+]CC(C)C)C(C)C.Cl.CC[O:41]CC>>[CH:25]1([CH2:24][C:8]2[C:7]([CH:3]([CH:1]=[O:41])[CH2:4][CH:5]=[CH2:6])=[C:12]([C:13]([F:15])([F:16])[F:14])[N:11]=[C:10]([CH:17]([F:18])[F:19])[C:9]=2[C:20]([O:22][CH3:23])=[O:21])[CH2:26][CH2:27]1
Reactant: CCOCC
Reactant: C=CCC(C#N)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC1CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Product: C=CCC(C=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC1CC1
Reaction time: 0.5 h

Procedure:
To a solution of 16.5 g (68.3 mmol) of methyl 5-(1-cyano-3-butenyl)-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 16 of U.S. Pat. No. 5,169,432) in 250 ml of ether cooled in an ice bath was added 91 ml (136 mmol) of diisobutylaluminum hydride (1.5 M in toluene). The reaction mixture was stirred on an ice bath for 30 min and was treated with 200 ml of 2.4 M HCl. The organic layer was washed with brine, dried (MgSO4), and filtered through silica gel. The filtrate was concentrated in vacuo and the residue was purified by HPLC (17% EtOAc in hexane) to give 8.1 g of methyl 4-(cyclopropylmethyl)-2-(difluoromethyl)-5-(1-formyl-3-butenyl)-6-(trifluoromethyl)-3-pyridinecarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[CH:18][NH:19]4)=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].O[CH2:25][CH2:26][C:27]1[S:31][CH:30]=[N:29][C:28]=1[CH3:32]>>[CH3:23][O:22][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:25][CH2:26][C:27]1[S:31][CH:30]=[N:29][C:28]=1[CH3:32])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: Cc1ncsc1CCO
Reactant: COc1cc2c(Nc3ccc4cc[nH]c4c3)ncnc2cc1O
Product: COc1cc2c(Nc3ccc4cc[nH]c4c3)ncnc2cc1OCCc1scnc1C
Yield: 34 %

Procedure:
Using an analogous procedure to that described in Example 201, 7-hydroxy-4-(indol-6-ylamino)-6-methoxyquinazoline (98 mg, 0.32 mmol), (prepared as described for the starting material in Example 217), was reacted with 5-(2-hydroxyethyl)-4-methylthiazole (69 mg, 0.48 mmol) to give 6-methoxy-4-(indol-6-ylamino)-7-(2-(4-methylthiazol-5-yl)ethoxy)quinazoline (47 mg, 34%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)[CH3:3].CCN(CC)CC.[C:22](Cl)([CH3:24])=[O:23]>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([NH:13][C:22](=[O:23])[CH3:24])[CH2:11][CH2:12]1)[CH3:3]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](NC(C)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(trans-4-Amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (10.0 g, 45 mmol, intermediate B) was dissolved in CH2Cl2 (150 ml) and Et3N and AcCl (3.89 g, 50 mmol) were added. The reaction mixture was stirred 3 h at room temperature before washing it with H2O and brine. After drying (Na2SO4) the solvent was evaporated to yield 8.42 g (82%, 37 mmol) of a white solid. MS (m/z): 228.3 ([M+H]+).
Reaction SMILES: [C:1]1(=O)[C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.C([Li])CCC.CCCCCC.[NH4+].[Cl-]>C(O)(C)C>[CH2:7]1[C:6]2[C:10](=[CH:11][C:12]3[CH2:1][CH:2]=[CH:3][C:4]=3[CH:5]=2)[CH2:9][CH2:8]1
Reactant: O=C1CCc2cc3c(cc21)CCC3
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)O
Solvent: CCCCCC
Product: C1=Cc2cc3c(cc2C1)CCC3
Temperature: 25 °C

Procedure:
The mixture of 3,5,6,7-tetrahydro-s-indacen-1(2H)-one (12.4 g, 0.072 mol), p-toluenesulfonyl hydrazide (13.4 g, 0.072 mol), 0.5 g TSA and i-propanol (100 ml) was refluxed by 5 min, and cooled to room temperature. Precipitate was filtered, washed by MeOH and dried, given 21 g of product (90%). Suspension of obtained hydrazone in 250 ml abs. Et2O was cooled to −70° C. and was treated with 15% n-butyllithium in hexane (100 ml. 0.16 mol). The resulting mixture was allowed to warm up to r.t. and refluxed until gas evolution. Reaction mixture was treated with 50 ml NH4Cl (10%), washed by water and dried. Solvent was evaporated, the residue was extracted by hot hexane, and to give after evaporation 9.1 g of solid product (81%).