Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([F:27])=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:27][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[N:1]=[CH:11][CH:12]=2)=[CH:20][C:19]=1[N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CN(C)C=CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Reactant: N#Cc1cn[nH]c1N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(c1cc(-c2ccnc3c(C#N)cnn23)ccc1F)S(C)(=O)=O
Yield: 71.1 %

Procedure:
A mixture of 0.036 g (0.33 mmol) of 5-amino-1H-pyrazole-4-carbonitrile and 0.1 g (0.33 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-methanesulfonamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 81 mg of N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 70%).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[F:17][C:18]([F:34])([F:33])[C:19]1[CH:32]=[CH:31][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:21][CH:20]=1>>[F:17][C:18]([F:33])([F:34])[C:19]1[CH:32]=[CH:31][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:21][CH:20]=1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Reactant: NCCCCCCOc1ccc(C(F)(F)F)cc1
Product: O=c1c(NCCCCCCOc2ccc(C(F)(F)F)cc2)c(Nc2ccncc2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 6-(4-trifluoromethylphenoxy)-hexylamine. The reaction mixture was heated to reflux for 4 hours instead of stirring 18 h at r.t.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=O.O.[NH2:16][NH2:17]>CO>[CH3:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([NH:16][NH2:17])=[O:2])[CH:13]=2)[CH:9]=[CH:10]1
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ccc2ccc(C(=O)NN)cc21

Procedure:
A mixture of 1-methyl-1H-indole-6-carboxylic acid methyl ester (3.2 g, 16.1 mmol), hydrazine monohydrate (8.5 g, 169 mmol) and methanol (50 ml) was stirred reflux for 15 h. The mixture was evaporated, water was added and the product was isolated by extraction with chloroform, followed by evaporation.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#N.CN.C(OC)(=O)C1[C:17](=CC=CC=1)[NH2:18]>C(O)C>[NH2:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:18][CH:17]=[CH:4]2
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: COC(=O)c1ccccc1N
Agent: CN
Solvent: CCO
Product: Nc1ccc2[nH]ccc2c1

Procedure:
Compound 245 was prepared using methods shown in Example 1, wherein 2-fluoro-5-nitrobenzonitrile and methylamine were used in Step A and methyl anthranilate was used in Step D. Reduction of the 5-nitro group was carried out using stannous chloride in ethanol to provide the corresponding 5-amino indole intermediate. Dimethylation of the 5-amino group was carried out using aqueous formaldehyde solution (37% w/w, 10 eq.) and MP-cyanoborohydride resion (2.42 mmol/g, 1.5 eq.) in methanol:acetic acid (9:1, v/v) at room temperature for about 15 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH2:52]([N:59]=[C:60]=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:60]([NH:59][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:61])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: O=C=NCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)NCc3ccccc3)cc2)C1=O

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]-methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and benzyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.38 (s, 6H), 1.82 (m, 1H), 2.15-2.55 (m, 3H), 4.14 (s, 2H), 4.24 (s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.32 (d, 15 Hz, 1H), 7.05-7.42 (m, 22H). FAB-MS: calculated for C44H45N5O5 723; found 724 (M+H, 100%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH3:38])[CH2:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[CH3:38][N:25]([CH3:24])[CH2:26][CH2:27][CH2:28][N:29]([C:30]1[CH:31]=[CH:32][C:33]([NH:36]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:34][CH:35]=1)[CH3:37]
Reactant: CN(C)CCCN(C)c1ccc(N)cc1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CC/C(Nc1ccc(N(C)CCCN(C)C)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-(3-dimethylaminopropyl)-N-methyl-p-phenylenediamine
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[Cl:17][C:18](OC(Cl)(Cl)Cl)=[O:19]>O1CCCC1>[Cl:17][C:18]([O:1][C@@H:2]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:19]
Reactant: CC(C)C[C@H](O)C(=O)OCc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C[C@H](OC(=O)Cl)C(=O)OCc1ccccc1

Procedure:
To a solution of benzyl (2S)-2-hydroxy-4-methylvalerate (1.00 g) in tetrahydrofuran (20 ml) was added trichloromethyl chloroformate (0.55 ml) at room temperature. The solution was refluxed for 11 hours and the solvent was removed by evaporation at atmospheric pressure to give benzyl (2S)-2-chlorocarbonyloxy-4-methylvalerate (1.26 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-])=O.[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([S:11]([C:16]2([Cl:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:17]2[NH2:18])(=[O:13])=[O:12])=[CH:5][C:4]=1[NH2:1]
Reactant: Nc1ccccc1Cl
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1cc(S(=O)(=O)C2(Cl)C=CC=CC2N)ccc1Cl
Yield: 14.7 %

Procedure:
A solution of 3-nitro-4-chlorobenzenesulphonyl chloride (768 mg, 3.0 mmol), 2-chloroaniline (383 mg, 3.0 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and pyridine (0.30 ml, 3.6 mmol) in DCM (35 ml) was stirred at ambient temperature overnight. The solution was evaporated to dryness, the residue dissolved in EtOAc and washed with 1.0 M aqueous hydrochloric acid and brine, dried and evaporated to dryness. The residue was dissolved in EtOAc (30 ml) and hydrogenated over 10% Pd/C for 4 h at ambient temperature. The catalyst was removed by filtration and the EtOAc evaporated to dryness. The residue was purified by column chromatography on basic alumina using 5% methanol in EtOAc to give, as a solid, the title compound (140 mg, 0.44 mmol). MS: 315.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[C:36](=[O:45])[CH:35]=1>CN(C=O)C>[C:1]1([O:7][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37](=[O:44])[C:36](=[O:45])[CH:35]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=C(OCCCCCCI)c2ccccc2C1=O
Reactant: Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C1C=C(OCCCCCCOc2ccccc2)c2ccccc2C1=O
Reaction time: 48 h
Yield: 42.8 %

Procedure:
Phenol (28 mg, 0.3 mmol) was treated with tetrabutylammonium hydroxide (0.3 mL of 1.0 M solution in methanol) and the reaction mixture was concentrated to dryness in vacuo. Iodonaphtoquinone 5 (115 mg, 0.3 mmol) in DMF (3 mL) was added to the tetrabutylammonium salt, stirred for 48 h and quenched with H2O (10 mL). The product was extracted with CHCl3, the extract was washed with H2O, then brine, dried (Na2SO4), and purified by chromatography (5% EtOAc in benzene) to give 12 as a yellow solid (45 mg, 43%) 1H NMR (CDCl3) 8.13 (d, J=7.4 Hz, 1H), 7.86 (d, J=7.4 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.15-7.40 (m, 2H), 6.85-7.10 (m, 3H), 5.96 (s, 1H), 4.17 (t, J=6.5 Hz, 2H), 3.99 (t, J=6.2 Hz), 1.70-2.10 (m, 4H), 1.35-1.70 (m, 4H).
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=1)[C:3](OCC)=[O:4].[H][H]>CO.[Pd]>[OH:1][CH:2]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=2)[NH:15][C:3]1=[O:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(O)Cc1nc(OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(n1)CC(O)C(=O)N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A roundbottom flask was charged with a solution of ethyl 2-hydroxy-3-(6-methoxy-3-nitropyridin-2-yl)propanoate (37 mmol) in methanol (500 ml). To the mixture was added 10% palladium on carbon (3 g). The solution was shaken under 40 psi of hydrogen for 12 hours. The resulting solution was then allowed to react, with stirring, for 5 hours while the temperature was maintained at room temperature. The mixture was then filtered and the filtrate was diluted with 100 ml of water. Hydrochloric acid was added until the pH=5. The mixture was filtered and the filtrate was adjusted to pH=8 by the addition of sodium carbonate. The solids that formed were collected by filtration to afford the title compound.
Reaction SMILES: [H][H].[F:3][C:4]1[CH:5]=[C:6]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O>[Pd].O1CCCC1>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:5][C:4]=1[F:3]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-n2cncn2)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(-n2cncn2)cc1F

Procedure:
Hydrogen was introduced under atmospheric pressure into the mixture consisting of 260 mg of 1-(3-fluoro-4-nitrophenyl)-1H-[1,2,4]triazole, 30 mg of Pd/C and 30 ml of tetrahydrofuran until the theoretical amount had been taken up. After filtering off the catalyst with suction and concentrating the mixture under reduced pressure, the remaining oily residue was purified by column chromatography (solvent: 98:2 dichloromethane:methanol; silica gel).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccc(Cl)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-chlorophenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.4 g, 97%): 1H NMR (300 MHz, CDCl3) δ 8.06 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.7 Hz, 2H), 7.21 (d, J=7.7 Hz, 2H), 6.81-6.51 (m, 8H), 6.41 (s, 1H), 5.70-5.44 (m, 1H), 3.20-2.82 (m, 2H); ESIMS m/z 518 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH2:22][NH2:23])=[CH:7]2.CCN(C(C)C)C(C)C.Cl[C:34]1[N:42]=[CH:41][N:40]=[C:39]2[C:35]=1[NH:36][CH:37]=[N:38]2>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:19])[F:20])[C:8]([CH2:22][NH:23][C:34]1[N:42]=[CH:41][N:40]=[C:39]3[C:35]=1[N:36]=[CH:37][NH:38]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Cc1cccc2cc(CN)c(-c3ccccc3C(F)(F)F)nc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure H using (8-methyl-2-(2-(trifluoromethyl)-phenyl)quinolin-3-yl)methanamine (0.1 g, 0.316 mmol, 1 eq) in EtOH (2 mL) was treated with iPr2NEt (0.07 mL, 0.4 mmol, 1.2 eq) followed by 6-chloropurine (0.049 g, 0.317 mmol, 1 eq). After purification, N-((8-methyl-2-(2-(trifluoro-methyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine as yellow syrup. The yellow syrup was triturated with CH2Cl2 and filtered to provide N-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=91 nM] as yellow syrup. 1H NMR (DMSO-d6) δ ppm 12.93 (1 H, s), 7.98-8.31 (4 H, m), 7.90 (1 H, d, J=7.8 Hz), 7.74-7.82 (2 H, m), 7.69 (2 H, t, J=6.5 Hz), 7.59 (1 H, d, J=7.0 Hz), 7.42-7.52 (1 H, m), 4.42-4.77 (2 H, m), 2.62 (3 H, s). Mass Spectrum (ESI) m/e=435.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([NH2:26])([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[CH3:17][C:18]([NH:26][C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CC(C)(N)c1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)CCNC(=O)OCc1ccccc1)c1ccccc1
Yield: 55.6 %

Procedure:
6.6 g of N-benzyloxycarbonyl-β-alanine, 4.0 g of α,α-dimethylbenzylamine and 7.4 g of triethylamine were dissolved in 400 ml of anhydrous methylene chloride. To this solution were then added 8.8 g of 2-chloro-1-methylpyridinium iodide slowly at room temperature, and the mixture was heated under reflux for 2 hours. The reaction mixture was then washed, in turn, with a 10% w/v aqueous solution of sodium hydroxide, with a 1N aqueous solution of hydrochloric acid and with a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. The solution was concentrated by evaporation under reduced pressure, to give 10.7 g of crude crystals. Recrystallization of these from a mixture of hexane and benzene afforded 5.6 g (yield 56%) of the title compound melting at 96°-97° C.
Reaction SMILES: [Cl:1][C:2]1([C:7]([O:9]CC)=O)[CH2:4][C:3]1([Cl:6])[Cl:5].[NH2:12][NH2:13]>C(O)C>[Cl:1][C:2]1([C:7]([NH:12][NH2:13])=[O:9])[CH2:4][C:3]1([Cl:6])[Cl:5]
Reactant: CCOC(=O)C1(Cl)CC1(Cl)Cl
Reactant: NN
Solvent: CCO
Product: NNC(=O)C1(Cl)CC1(Cl)Cl

Procedure:
A solution of ethyl 1,2,2-trichlorocyclopropane carboxylate (3 grams), ethanol (25 ml), and anhydrous hydrazine (0.48 grams) was heated to reflux for approximately 2 hours. The reaction mixture was cooled, the solvent was stripped from solution, and the residue was recrystallized using a small volume of ethanol to produce 1,2,2-trichlorocyclopropane carboxylic acid hydrazide (mp 122°-123° C.). The identity of the final product was confirmed by NMR analysis.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=1>>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=5)[C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cccc(CBr)c1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Product: Cc1cccc(CN2Cc3ccc(N4CCN(CCC(c5ccccc5)c5ccccc5)CC4)cc3C2=O)c1
Yield: 101.3 %

Procedure:
In the same manner as in Example 51, the title compound (48 mg) was prepared from the compound (50 mg) obtained in Example 50 and α-bromo-m-xylene (17 mg).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C:4]([C:7]([O-:9])=[O:8])=[CH:3]1.[Na+].[H][H]>O.[Pd]>[O:1]=[C:2]1[O:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C1C=C(C(=O)[O-])CO1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: O=C1CC(C(=O)O)CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.8 %

Procedure:
To a solution of sodium 5-oxo-2,5-dihydrofuran-3-carboxylate (150 mg) in water (3 ml) was added 10 wt % palladium on carbon (30 mg), and the mixture was stirred for 18 hours at room temperature under one atm. of hydrogen. Under nitrogen atmosphere, an appropriate amount of amberlite IR-120 was added to the reaction solution, the mixture was stirred at room temperature for 10 minutes, and then filtered through Celite. The filtrate was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, the mixture was dried over sodium sulfate, and then again concentrated under reduced pressure to give the titled compound (83 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[CH3:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH:4]([CH2:3][CH2:2][N:28]3[C:27]([CH3:26])=[N:31][N:30]=[N:29]3)[CH2:8][CH2:7]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Reactant: Cc1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3nnnc3C)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=430.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 5-methyl-1H-tetrazole.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C1COCC1>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:5]=1
Reactant: C1COCCN1
Reactant: Fc1ccc(CBr)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc(CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
A solution of 5-(bromomethyl)-2-fluoropyridine (26.000 g, 137 mmol) in THF (30 mL) was cooled to −30° C. and morpholine (17.88 mL, 205 mmol) was slowly added. After min, triethylamine (57.2 mL, 410 mmol) was slowly added. Following addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature. After 30 min, the mixture was filtered through a fine-fritted funnel and the filtrate was concentrated to give an orange oil. The crude material was purified by chromatography through a Thompson Instruments pre-packed silica gel (330 gram) column eluting with a gradient of 0% to 100% EtOAc in hexane over 50 min to give 4-((6-fluoropyridin-3-yl)methyl)morpholine (15.767 g, 80 mmol, 58.7% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H); 7.79 (td, J=8.07, 2.45 Hz, 1H); 6.90 (dd, J=8.31, 2.84 Hz, 1H); 3.67-3.72 (m, 4H); 3.49 (s, 2H); 2.39-2.48 (m, 4H). m/z (ESI, +ve ion) 197.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:24])[CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:7]=1.CN([CH:28]=[O:29])C>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[CH:7]=[C:6]([NH:5][CH2:4][CH:3]3[O:24][C:28](=[O:29])[NH:1][CH2:2]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc(NCC(O)CN)c3ccccc3n2)cc1
Product: COc1ccc(-c2cc(NCC3CNC(=O)O3)c3ccccc3n2)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a 0° C. solution of (RS)-1-amino-3-[2-(4-methoxy-phenyl)-quinolin-4-ylamino]-propan-2-ol (0.139 g) 0.429 mmol) in DMF (2.5 ml) was added dropwise a solution of 1,1-carbonyldiimidazole (0.076 g, 0.472 mmol) in DMF (1 ml). After 20 min. at 0° C., and 1.5 hours at 60° C., the reaction mixture was cooled to room temperature and concentrated. Addition of H2O provided (RS)-5-{[2-(4-methoxy-phenyl)-quinolin-4-ylamino]-methyl}-oxazolidin-2-one (0.110 g, 73%) as yellowish solid, MS: m/e=349 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH3:18][N:19]1[C:23]([CH3:24])=[CH:22][C:21]([C:25](O)=[O:26])=[N:20]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:21]3[CH:22]=[C:23]([CH3:24])[N:19]([CH3:18])[N:20]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: Cc1cc(C(=O)O)nn1C
Product: Cc1cc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OC[C@@H]3F)c2)nn1C

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (CAS 5744-59-2) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=364.3 [M+H]+