Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[CH3:23][N:24]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:25](=[O:27])[CH3:26].N12CCCN=C1CCCCC2>CN(C)C=O>[CH3:23][N:24]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:32])[C:25](=[O:27])[CH3:26]
Reactant: CC(=O)N(C)CCCC(=O)O
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)N(C)CCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 22.8 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 4-(N-methylacetamido)butanoic acid (4.8 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g). The oily residue obtained is purified by chromatography on silica (0.063-0.2 mm; 150 g) contained in a column 3 cm in diameter [eluant: methylene chloride/methanol (99:1 by volume)] and collecting 30-cc fractions. Fractions 76 to 175 are concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. and, after crystallization in ethyl ether, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-(N-methylacetamido)butyrate (3.1 g), m.p. 170° C., is obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]3[CH2:17][CH:16]3[CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)[CH:8]=[CH:7]1.CN([CH:25]=[O:26])C>>[CH3:20][N:19]([CH2:18][CH:16]1[CH2:17][CH:15]1[C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH:25]=[O:26])=[CH:7][NH:6]2)=[CH:10][CH:11]=1)[CH3:21]
Reactant: CN(C)C=O
Reactant: CN(C)CC1CC1c1ccc2cc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CC1CC1c1ccc2c(C=O)c[nH]c2c1
Reaction time: 0.25 h

Procedure:
Phosphorous oxychloride (0.23 g, 1.47 mmol) was added to dimethylformamide (2 mL) at room temperature with stirring. After 15 min, [2-(1H-indol-6-yl)-cyclopropylmethyl]-dimethyl-amine (0.35 g, 1.64 mmol) in DMF (3 mL) was added dropwise. After 20 h, the reaction was quenched with ice and 1 N NaOH. The solution was extracted with methylene chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 6-(2-dimethylaminomethyl-cyclopropyl)-1H-indole-3-carbaldehyde of an oil (0.25 g, 63%) that was used for the next reaction without purification. 1H NMR (CDCl3): δ9.84 (s, 1H), 8.14 (d, J=8.4 Hz, 1H), 7.97 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.05 (s, 1H), 2.64 (s, 1H), 2.56 (s, 7H), 1.91 (m, 1H), 1.27 (m, 1H), 1.06 (m, 1H), and 0.92 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=3)[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH-:25].[Na+].OO>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:24])=[O:25])[CH:18]=3)[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(-c2nc(-c3cccc(O)c3)nc3ccsc23)ccn1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cc(-c2nc(-c3cccc(O)c3)nc3ccsc23)ccn1
Reaction time: 8 h

Procedure:
A mixture of 4-[2-(3-hydroxy-phenyl)-thieno[3,2-d]pyrimidin-4-yl]-pyridine-2-carbonitrile, (48 mg), sodium hydroxide (1M, 0.3 mL) and aqueous hydrogen peroxide (30%, 0.1 mL) was stirred in methanol (3 mL) at room temperature. After stirring overnight, the reaction mixture was concentrated in vacuo, neutralised with HCl (2M), and diluted with water, yielding a precipitate. This was collected by filtration and purified using flash chromatography to yield the title compound (29 mg).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:38])[C:29]3[N:33]=[C:32]([CH:34]4[CH2:36][CH2:35]4)[NH:31][C:30]=3[CH:37]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:34]1([C:32]2[NH:31][C:30]3[CH:37]=[C:26]([O:25][C:21]4[N:22]=[CH:23][N:24]=[C:19]([N:14]5[CH2:13][CH2:12][C:5]6([O:4][C:3](=[O:17])[NH:2][C:7]7[N:8]=[CH:9][CH:10]=[CH:11][C:6]6=7)[CH2:16][CH2:15]5)[CH:20]=4)[CH:27]=[C:28]([CH3:38])[C:29]=3[N:33]=2)[CH2:35][CH2:36]1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c(C3CC3)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2[nH]c(C3CC3)nc12

Procedure:
41 mg (0.16 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 40 mg (0.13 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-cyclopropyl-4-methyl-1H-benzo[d]-imidazole and 0.08 mL (0.48 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[C:7]([F:13])[CH:6]=1>CN(C=O)C>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[C:7]([F:13])[CH:6]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)cc1F
Temperature: 26 °C
Reaction time: 10 h
Yield: 88.1 %

Procedure:
A suspension of NaCN (2.085 g, 42.5 mmol) in DMF (20 mL) was added to a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (5.7 g, 21.27 mmol) in DMF (20 mL). The mixture was stirred at 26° C. for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74 mmol, 88.0% yield) was used to next step without further purification. TLC (PE/EA=1/1, Rf 0.5): 1H NMR (400 MHz, CDCl3) δ 7.24-7.37 (m, 3H), 3.70 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])=[CH:4][C:3]=1[F:22].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C@@H:6]([OH:7])[C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:4][C:3]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(Cl)c(F)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@H](O)c1ccc(Cl)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
(R)-tert-Butyl 2-(4-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate (1.12 g, 3.42 mmol) was placed in THF (50 mL) at −78° C., and 1.0M L-Selectride® (5.13 mL, 5.13 mmol) as a solution in THF was added. The reaction was stirred at −78° C. for 1 hour and then 0° C. for 2 hours. The reaction was quenched with 1N HCl, and the pH was adjusted to about 7 with saturated NaHCO3. The mixture was concentrated to remove most of the THF, and the residue was extracted with ethyl acetate (2×). The combined organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (12:1) to give (R)-tert-butyl 2-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (0.67 g, 60%). m/z (APCI-pos) (M+1)-Boc=230.1, 232.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:11])[CH:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[NH2:11]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.), stirred solution of 4-fluoro-2-aminobenzoic acid (2.68 g; 17.3 mmol) in dry tetrahydrofuran (60 mL) and MeOH (10 mL) was added a solution of trimethylsilyldiazomethane in hexanes (12 mL of 2.0 N; 24 mmol) via syringe over 20 minutes under nitrogen atmosphere. The resulting solution was allowed to warm to room temperature and stirred for 2 hours then concentrated in vacuo to provide the ester a light yellow solid (˜100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.[C:30]1([C@@H:36]([CH3:39])[CH2:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:9][NH:8][C:6]1[N:7]=[C:2]([NH:38][CH2:37][C@@H:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:39])[N:3]=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:27])[F:28])=[O:17])[CH2:14][CH2:15]2)[N:5]=1
Reactant: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Reactant: C[C@@H](CN)c1ccccc1
Product: CNc1nc(NC[C@H](C)c2ccccc2)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Temperature: 80 °C

Procedure:
Approximately half of the suspension prepared in step c was treated with (2R)-2-phenylpropylamine (1.16 mL, 8.14 mmol, 10.0 equiv). After heating to 80° C., the solvents were removed in vacuo, and the residue was purified by reverse-phase HPLC (Sunfire, 35-60% CH3CN/H2O, 0.1% TFA, 12 min) to afford 156 mg of the title compound. MS (ES+): m/e 528.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:13]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>>[CH3:36][O:35][C:33](=[O:34])[CH2:32][NH:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]2[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: COC(=O)CBr
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
4-(2,4-Dichloro-phenyl)-1-(4-nitro-phenyl)-2-(4-bromo-benzyl)-1H-imidazole (5.0 g, 10 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10]Br)=[C:6]([CH2:14][CH2:15][CH3:16])[C:5]=1[OH:17])(=[O:3])[CH3:2].[SH:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][S:18][C:19]2[NH:20][C:21]3[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[C:6]([CH2:14][CH2:15][CH3:16])[C:5]=1[OH:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2nc(S)[nH]c2c1
Reactant: CCCc1c(OCCBr)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCSc2nc3ccc(C(=O)OCC)cc3[nH]2)ccc(C(C)=O)c1O
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
A mixture of 2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethyl bromide (2.71 g), ethyl 2 mercaptobenzimidazole-5-carboxylate (2.00 g) and anhydrous potassium carbonate (1.49 g) in N,N-dimethylformamide (30 ml) was stirred at 80-90 ° C. for 30 minutes. The reaction mixture was poured into ice-water, made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with dichloro-methane-ethyl acetate (10:1), to give ethyl 2-[2-(4-acetyl-3- hydroxy-2-propylphenoxy)ethylthio]benzimidazole-5-carboxylate (2.33 g, 58.5 %) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[O:25][C:24](=[O:32])[NH:23][C:22]=3[CH:21]=2)[CH2:11][CH2:10]1>CCO.C1COCC1.CCOC(C)=O.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[CH:28][C:27]3[C:26]([CH3:30])([CH3:31])[O:25][C:24](=[O:32])[NH:23][C:22]=3[CH:21]=2)[CH2:11][CH2:10]1
Reactant: CC1(C)OC(=O)Nc2cc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ncc21
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2cc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ncc21
Yield: 44.2 %

Procedure:
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one (452 mg, 0.95 mmol) was hydrogentated using Ra—Ni in EtOH/THF. The reaction was filtered and concentrated. Purification by liquid chromatography (5% MeOH/CH2Cl2 with 0.5% NH4OH) gave a white foam (385 mg, 85% pure). The foam was dissolved in a minimal amount of EtOAc and, upon standing, a white precipitate formed. The precipitate was filtered and washed with Et2O to give the title compound as a white solid (200 mg, 0.42 mmol, 44%). MS: APCI: M+1: 477.1 (Exact Mass: 476.17).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]2[CH2:23][CH2:24][CH:19]([N:14]3[CH:15]=[CH:16][C:17](=[O:18])[C:12]([C:11]4[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=[CH:9][CH:10]=4)=[N:13]3)[CH2:20][CH2:21]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=c1ccn(C2CCNCC2)nc1-c1ccnn1-c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1ccn(C2CCN(c3ccc(F)cc3)CC2)nc1-c1ccnn1-c1ccccc1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A suspension of 3-(1-phenyl-1H-pyrazol-5-yl)-1-piperidin-4-ylpyridazin-4(1H)-one (0.30 g), 1-bromo-4-fluorobenzene (0.21 mL), Pd2(dba)3 (43 mg), X-phos (45 mg) and sodium tert-butoxide (135 mg) in toluene (10 mL) was stirred at 120° C. for 5 hr under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to give the title compound (0.32 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH2:10][CH:9]1[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][C@H:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[CH3:18]>>[CH2:1]([N:8]1[CH2:11][CH2:10][CH:9]1[C:12]([NH:16][C@H:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[CH3:18])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)C1CCN1Cc1ccccc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2CCN2Cc2ccccc2)cc1
Yield: 53.2 %

Procedure:
The title compound (D76) (98 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 1-benzylazetidine-2-carboxylic acid (100 mg, available from Apollo#OR7040) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (113 mg). Reaction time: 1 h
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:29](=[O:37])[N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:28]=[CH:27][C:16]([C:17]([O:19]CC4C=CC=CC=4)=[O:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[N:8]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[CH2:3][C:4]([C:29](=[O:37])[N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:28]=[CH:27][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCc4ccccc4)cc3)cc2N=C(N)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)O)cc3)cc2N=C(N)C1

Procedure:
Benzyl 4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoate (0.025 g, 0.0504 mmol) was suspended in 1 ml of methanol, and 25 mgs of 10% Pd/C (Degussa type) was added and the mixture was hydrogenated under a balloon of hydrogen for one hour. This mixture was then filtered through GF/F filter paper, and the filtrate was concentrated to 16 mgs of 4-((1E,4E)-2-amino-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-8-yl)benzoic acid (78%). 1H NMR (400 MHz, DMSO-d6) δ 7.98-8.03 (m, 2H), 7.76-7.82 (m, 2H), 7.38-7.43 (m, 1H), 7.33-7.37 (m, 1H), 7.27-7.31 (m, 1H), 6.92 (br s, 1H), 6.76 (s, 1H), 3.28-3.36 (m, 4H, partially obscurred by water peak), 2.74 (s, 2H), 1.51-1.62 (m, 4H), 0.71-0.97 (m, 6H); m/z (APCI-pos) M+1=406.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12]>CCOC(C)=O.[OH-].[Pd+2].[OH-]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([OH:12])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1cc(O)c(F)cc1F
Reaction time: 6 h
Yield: 95.5 %

Procedure:
To a suspension of 2,4-difluoro-5-nitrophenol (1.01 g, 5.77 mmol) in EtOAc was added palladium hydroxide (0.08 g, 0.57 mmol) and the resulting slurry was stirred under a hydrogen atmosphere for 6 h. The mixture was filtered through a Celite® pad, washing with EtOAc (2×10 mL) and the filtrate was concentrated to afford 5-amino-2,4-difluorophenol (0.8 g, 96% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 6.91 (t, J=7.2 Hz, 1H), 6.35 (t, J=8.8 Hz, 1H), 4.84 (brs, 2H); MS (ESI) m/z: 146.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C1(P(=[CH:32][CH:33]=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5](/[CH:6]=[CH:32]/[CH:33]=[O:34])[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=C/C=C/c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Trifluoromethylbenzaldehyde (20.0 g, 0.115 mol) was taken up in 500 mL of CH3CN along with (triphenylphosphoranylidene)acetaldehyde (35 g, 0.115 mol). The reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in 800 mL of 1:1 pentane/EtOAc and filtered. The filtrate was concentrated under reduced pressure to afford crude (E)-3-(3-(trifluoromethyl)phenyl)acrylaldehyde as a dark red oil. This material was taken up in 30 mL of CH2Cl2. The resulting mixture was slowly added to a suspension of 2-nitroaniline (4 g, 0.029 mol) in concentrated HCl (50 mL) at 90° C. over a period of 30 min. The resulting reaction mixture was stirred at 90° C. for an additional 1 h. The reaction mixture was cooled to room temperature and washed with CH2Cl2 (2×100 mL). The aqueous layer was neutralized with 5% aqueous NaOH and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (pentane/EtOAc) to afford 800 mg of 8-nitro-2-(3-(trifluoromethyl)phenyl)quinoline. MS (ESI) calcd for C16H9F3N2O2 (m/z): 318.06. found: 319 [M+1].
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH2:35][Br:36])[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:38]>C(O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH2:35][Br:36])[C:27]([O-:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:38]
Reactant: CCOC(=O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
28.2 g of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(2-bromoethoxyimino)-acetate were added to a mixture of 6 g of sodium hydroxide pastilles in 280 ml of absolute ethanol and the mixture was stirred at room temperature for 65 hours and was vacuum filtered. The recovered product was washed with ethanol and dried under reduced pressure to obtain 29.2 g of the syn isomer of sodium 2-(2-tritylamino-4-thiazolyl)-2-(2-bromoethoxyimino)-acetate, solvated at 12%.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([NH:35][NH2:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[C:25]1([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:36]2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc2ccccc12
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and naphthalen-1-yl-hydrazine according to the method described for example 1. MS: M=433.2 (M+H)+
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:15][C:16]1[N:20]([CH3:21])[N:19]=[C:18]([O:22][CH3:23])[C:17]=1[C:24]1[CH:32]=[CH:31][C:27]2[O:28][CH2:29][O:30][C:26]=2[CH:25]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([C:17]3[C:18]([O:22][CH3:23])=[N:19][N:20]([CH3:21])[C:16]=3[NH:15][S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])=[CH:25][C:26]=2[O:30][CH2:29]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1nn(C)c(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.5 %

Procedure:
To a solution of 4-dimethylaminopyridine in anhydrous pyridine at 0° C. under an atmosphere of nitrogen was added 4-(trifluoromethyl)benzenesulfonyl chloride (148 mg) in pyridine (1.5 ml). After 10 min the reaction was treated with 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazole (Preparation 43) (100 mg) and the reaction was allowed to warm to room temperature and stirred for 12 h. The reaction was concentrated under reduced pressure, the residue treated with 1.0M aqueous citric acid (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (eluent of 55% water in acetonitrile to 30% water in acetonitrile over 8 mins, then 30% water in acetonitrile for 13 mins. Phenomenex Magellen™ 150 mm×21.5 mm column, 40° C.) to yield the title compound as an off-white solid (1 mg).