Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([O:18][C:19]4[C:24]([CH:25]=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=4)=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[CH3:27][Mg]Br.O>O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([O:18][C:19]4[C:24]([CH:25]([OH:26])[CH3:27])=[CH:23][CH:22]=[CH:21][N:20]=4)=[C:13]([C:14]([F:16])([F:15])[F:17])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: O=Cc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cccnc1Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-{[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]oxy}pyridine-3-carbaldehyde (417, 20 mg, 0.055 mmol, 1 equiv.) was dissolved in tetrahydrofuran (2 mL), cooled to 0° C. and treated with methylmagnesium bromide (28 μL, 0.083 mmol, 1.5 equiv). After stirring for 30 minutes, the mixture was poured into water (10 mL) and was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC (gradient 80:20 to 5:95; water containing 0.05% trifluoroacetic acid:acetonitrile containing 0.05% trifluoroacetic acid) to provide the titled compound 418. High resolution mass spectrometry (ES+) m/z=379.1374, [(M+H)+ calculated for C18H18F3N4O2: 379.1376].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12]O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CCO)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCCl)cc1OC

Procedure:
The reaction mixture of 2-(3,4-dimethoxyphenyl)ethanol (6.0 g, 32.8 mmol) and thionyl chloride (19 g, 164 mmol) in chloroform (20 mL) was stirred at reflux for 4 h, concentrated, and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO3 and brine, dried over anhydrous sodium sulfate, and concentrated to afford 4-(2-chloroethyl)-1,2-dimethoxybenzene (K) quantitatively (6.6 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N:10]#[C:11]Br>CCOCC.CCCCCC>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][N:6]=[C:11]=[NH:10])[CH3:2]
Reactant: N#CBr
Reactant: CCOC(CN)OCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(CN=C=N)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of the aminoacetaldehyde diethyl acetal (5.32 g, 40 mmol) in ether (20 mL) was added to a suspension of CNBr (4.22 g, 40 mmol) in hexane (20 mL) at RT. The reaction mixture was stirred at RT overnight. The solid was removed by filtration and washed with ether. The combined filtrate was concentrated. Flash chromatography of the concentrated residue afforded 2.82 g (45%) of the N-(2,2-diethoxyethyl)carbodiimide (a). 1H NMR (500 MHz, CDCl3): 4.58 (t, J=5.5 Hz, 1H), 3.85 (br s, 1H), 3.73 (m, 2H), 3.56 (m, 2H), 3.16 (J=5.5 Hz, 2H), 1.23 (t, J=7.0 Hz, 3H), MS: 156.8 (M−H)−; 180.9 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][NH:14][C@@H:13]([CH3:17])[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30](O)=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)=[O:10])[CH2:12][C@@H:13]3[CH3:17])=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(C(=O)N2CCN[C@@H](C)C2)n1
Reactant: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4cccc(Cl)c4)n3)[C@@H](C)C2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 71 mg (0.30 mmol) (6-methoxy-pyridin-2-yl)-((S)-3-methyl-piperazin-1-yl)-methanone, 67 mg (0.30 mmol) 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid, 0.11 g (0.33 mmol) TBTU and 77 μL (0.450 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:8]([O:10]CC)=[O:9])[N:6]=1.CN1C=CN=C1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOCc1ccc(F)cc1)c1csc(N)n1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccc(F)cc2)C(=O)O)cs1
Yield: 94.9 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(4-fluorobenzyloxyimino)-acetate (syn isomer, 25.5 g.), 1-methylimidazole (1.3 g.), 1N sodium hydroxide solution (118.3 ml.), methanol (250 ml.) and tetrahydrofuran (200 ml.) were treated in similar manner to that of Example p-(4) to give 2-(2-aminothiazol-4-yl)-2-(4-fluorobenzyloxyimino)acetic acid (syn isomer, 22.11 g.).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:22])[N:17]([CH:19]([CH3:21])[CH3:20])[N:18]=2)=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.[H-].[Na+].I[CH3:32].O>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:22])[N:17]([CH:19]([CH3:21])[CH3:20])[N:18]=2)=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][N:11]([CH3:32])[CH:12]=1
Reactant: CC(C)n1nc(-c2nc(-c3cn[nH]c3)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)n1nc(-c2nc(-c3cnn(C)c3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 6-[5-amino-3-phenyl-6-(1H-pyrazol-4-yl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (120 mg) was added to a suspension of NaH (60% in oil) (14.2 mg) and the mixture was stirred at 25-30° C. for 30 minutes. The mixture was cooled in an ice bath and iodomethane (0.1 ml) was added. The mixture was stirred at the same time for 30 minutes and at 20-30° C. for one hour. After addition of water (3.6 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel (EtOAc only) to give a solid. The solid was suspended in acetone and collected by filtration to give 6-[5-amino-6-(1-methyl-1H-pyrazol-4-yl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (70 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].[OH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19]>C1COCC1>[C:1]([O:5][C:6](=[O:9])[CH2:7][CH2:8][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCOCCOCCO
Reactant: C=CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCO
Reaction time: 8 h

Procedure:
Na metal (catalytic) was added to a stirring solution of acrylic acid tert-butyl ester (6.7 mL, 46 mmol), and 2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethanol (20.7 g, 138 mmol) in THF (100 mL) at 0° C. and the mixture was stirred overnight. Solvent was removed and the remaining oil dissolved in EtOAc (100 mL). The organic layer was washed with water (3×50 mL), and dried over Na2SO4 and the solvent removed in vacuo to give an oil which corresponds to the title compound that would be used as is for the next step. (M+1)=279.
Reaction SMILES: C([O:8][C:9]1[CH:57]=[CH:56][C:12]([CH2:13][C@H:14]([NH:28][C:29](=[O:55])[C:30]2[CH:53]=[C:52]([CH3:54])[CH:51]=[C:32]([C:33]([N:35]([CH2:39][CH2:40][CH2:41][CH2:42][O:43]CC3C=CC=CC=3)[CH2:36][CH2:37][CH3:38])=[O:34])[CH:31]=2)[C@H:15]([OH:27])[CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[OH:43][CH2:42][CH2:41][CH2:40][CH2:39][N:35]([CH2:36][CH2:37][CH3:38])[C:33](=[O:34])[C:32]1[CH:51]=[C:52]([CH3:54])[CH:53]=[C:30]([C:29]([NH:28][C@@H:14]([CH2:13][C:12]2[CH:56]=[CH:57][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:15]([OH:27])[CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:55])[CH:31]=1
Reactant: CCCN(CCCCOCc1ccccc1)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)[C@H](O)CNCc2cccc(OC)c2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCN(CCCCO)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2ccc(O)cc2)C(O)CNCc2cccc(OC)c2)c1
Reaction time: 5 h

Procedure:
A mixture of N1-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N3—-[4-(benzyloxy)butyl]-5-methyl-N3-propylisophthalamide (X, 100 mg, 0.130 mmol) and palladium on carbon (10%, 100 mg) in absolute glacial acetic acid (5 mL) is shaken under an atmosphere of hydrogen at 35 psi for 5 hours. The resulting mixture is filtered through diatomaceous earth and washed with methanol. The combined filtrates are concentrated under reduced pressure. The concentrate is purified by flash column chromatography (silica; gradent of dichloromethane/methanol/ammonium hydroxide 97/3/0.05 to 93/7/0.05) to give the title compound: NMR (300 MHz, CD3OD): δ 7.55–6.64, 4.19, 3.99–3.72, 3.63–3.36, 3.21–3.09, 2.79–2.69, 2.39, 1.90–1.40, 1.29 and 1.02–0.6; ESI-MS (m/z) [M+H]+=592.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([CH2:28][NH:29][CH:30]2[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]([CH:30]2[CH2:31][CH2:32]2)[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)=[CH:33][CH:34]=1
Reactant: Clc1ccc(CNC2CC2)cc1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCN(Cc3ccc(Cl)cc3)C3CC3)cn2)c1
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and (4-chlorobenzyl)cyclopropylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 0.17 (2H, m), 0.40 (2H, m), 1.83 (1H, m), 2.88 (2H, t, J=6.4 Hz), 3.72 (2H, s), 4.10 (2H, t, J=6.2 Hz), 7.26 (1H, d, J=8.4 Hz), 7.32 (2H, t, J=8.4 Hz), 7.45 (1H, dd, J=3.7 Hz), 7.64 (2H, d, J=4.4 Hz), 8.21 (1H, s), 8.31 (1H, s), 8.40 (1H, d, J=4.8 Hz). [M+H] Calc'd for C21H21ClN4O2, 398. Found, 398.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH3:18])[C:8]([CH3:17])=[C:9]([CH2:11][CH2:12][C:13]([O:15]C)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CO>[CH2:20]([NH:38][C:13](=[O:15])[CH2:12][CH2:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]([OH:19])=[C:7]([CH3:18])[C:8]=1[CH3:17])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Reaction time: 4 h

Procedure:
A mixture consisting of 10.6 grams of methyl 3-(5-tert.-butyl-2,3-dimethyl-4-hydroxyphenyl)propionate and 11.9 grams of n-octadecylamine were heated together for 1 hour at 160° to 165° and then at 175° to 180° for 4 hours, the methanol of reaction being removed continuously by distillation. Crystallization from methanol yielded white crystals melting at 85° to 87° (Compound 35).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[C:10]3[CH:17]=[CH:16][N:15]([Si](C(C)C)(C(C)C)C(C)C)[C:11]=3[N:12]=[CH:13][N:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CO>C(Cl)(Cl)Cl.CO>[CH:1]1([C:7]([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C3CCCCC3)ncnc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(c1ncnc2[nH]ccc12)C1CCCCC1
Yield: 69.2 %

Procedure:
Cyclohexyl[7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]methanone (22.4 mg, 58.0 μmol) was stirred with hydrogen chloride-methanol solution (10 wt %, 2.0 mL) at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hi Flash column amino type manufactured by Yamazen Corporation: chloroform/methanol=10/1 (v/v)) to give the title compound as a pale yellow oil (9.2 mg, yield 69%).
Reaction SMILES: Cl.[F:2][C:3]([F:11])([F:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(#N)C.[CH2:15]([O:17][C:18]([C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:35]Br)=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:15]([O:17][C:18]([C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:35][N:7]1[CH2:8][CH2:9][CH:4]([C:3]([F:11])([F:10])[F:2])[CH2:5][CH2:6]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Temperature: 40 °C
Yield: 80 %

Procedure:
To a solution of 107.7 g of 4-trifluoromethyl piperidine hydrochloride in 450 mL of water were added 2.7 L of acetonitrile, 224 g of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester and 157 g of potassium carbonate. The resulting mixture was heated to 40° C. for 2 h, allowed to cool to room temperature then concentrated under reduced pressure. The residue was taken into 2 L of dichloromethane then washed twice with 500 mL of water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/ethanol from 100/0 to 90/10) followed by washing of the collected solid with diisopropyl ether to give 212 g of 2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazole-5-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH:20]=O)[CH:18]=3)[S:13][C:6]=12.CC(O)=O.[CH3:33][NH:34][CH2:35][CH2:36][OH:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:34]([CH3:33])[CH2:35][CH2:36][OH:37])[CH:18]=3)[S:13][C:6]=12
Reactant: O=CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Reactant: CNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(CCO)CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 146 (810 mg, 2.033 mmol) in DCM (40 mL) was added HOAc (0.233 mL, 4.07 mmol) and 2-(methylamino)ethanol (305 mg, 4.07 mmol), and the reaction mixture was stirred at RT for an hour. Sodium triacetoxyborohydride (1.293 g, 6.10 mmol) was added and the mixture was stirred at RT overnight. The mixture was then diluted with saturated NaHCO3 solution then solid NaHCO3 was added to neutralize the acid. The DCM layer was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 147 (930 mg, 100% yield) that was used directly in the next step with no additional purification. MS (m/z)=458.50 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18]I.[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH2:17][CH3:18])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1C#N
Reactant: CI
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1nc(NC(=O)OC(C)(C)C)ccc1C#N
Yield: 77.3 %

Procedure:
To a stirred solution of 2-t-butoxycarbonylamino-5-cyano-6-methylpyridine (0.50 g, 2.145 mmol) in dry THF (15 ml) at -78° C. was added n-BuLl (1.75 ml, 2.5M in hexanes) dropwise. The solution turned deep red upon addition of the second equivalent of base. After 0.5 h methyl iodide (0.67 ml, 10.7 mmol) was added. After 1 h half saturated NH4Cl (15 ml) was added, the layers were separated and the aqueous layer was extracted with EtOAc (2×35 ml). The organic layers were combined and washed with saturated NaHCO3 (1×15 ml), water (1×15 ml), and brine (1×15 ml), dried over MgSO4, filtered and concentrated to an oil. The crude product was purified by flash column chromatography (95:5; hexanes: ethyl acetate) to give the title compound (0.41 g) as a solid: 1H NMR (CDCl3) δ 1.29 (t, J=7.5 Hz, 3 H), 1.53 (s, 9 H), 2.91 (q, J=7.6 Hz, 2 H), 7.40 (br s, 1H), 7.81 (d, J=8.6 Hz, 1 H), 7.87 (d, J=8.8 Hz, 1 H).
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:12]2[N:11]=[C:10]([SH:13])[NH:9][C:8]=2[CH:7]=[C:6]([O:14][CH3:15])[C:5]=1[O:16][CH3:17].Cl.Cl[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][N:23]=1.[OH-].[Na+]>O.C(O)C>[F:18][CH:2]([F:1])[O:3][C:4]1[C:12]2[N:11]=[C:10]([S:13][CH2:21][C:22]3[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][N:23]=3)[NH:9][C:8]=2[CH:7]=[C:6]([O:14][CH3:15])[C:5]=1[O:16][CH3:17]
Reactant: COc1ccnc(CCl)c1C
Reactant: COc1cc2[nH]c(S)nc2c(OC(F)F)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccnc(CSc2nc3c(OC(F)F)c(OC)c(OC)cc3[nH]2)c1C
Yield: 87.7 %

Procedure:
1.0 g of 4-difluoromethoxy-5,6-dimethoxy-1H-benzimidazole-2-thiol, 0.75 g of 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride, 0.3 g of sodium hydroxide, 2 ml of water and 10 ml of ethanol are stirred for 2.5 h at 60° C. The mixture is poured onto 100 ml of water and cooled in an ice bath. This gives 1.3 g (87%) of the title compound (m.p. 177°-179° C., from diisopropyl ether).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:25][CH:26]=1>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:25][CH:26]=1)[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: ClCc1coc(-c2ccccc2)n1
Product: CCOC(Cc1ccc2c(ccn2Cc2coc(-c3ccccc3)n2)c1)C(=O)O
Yield: 80 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-phenyl-oxazole, the title compound was obtained in 80% yield as a brown oil. MS: (M+H)+ 391.1.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[S:16][C:17]=2[CH3:18])=[CH:6][CH:5]=1.[NH2:30][NH2:31]>CO.O>[CH3:18][C:17]1[S:16][C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[N:14][C:13]=1[CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:30][NH2:31])=[O:2])=[CH:5][CH:6]=1
Reactant: NN
Reactant: COC(=O)c1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)sc2C)cc1
Solvent: CO
Solvent: O
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc(C(=O)NN)cc1
Temperature: 60 °C
Reaction time: 66 h
Yield: 66.2 %

Procedure:
To a suspension of 4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylethoxy]-benzoic acid methyl ester (Example 4, 410 mg, 1 mmol) in methanol (3 mL) add anhydrous hydrazine (0.32 ml, 10 mmol). Warm the resulting mixture to 60° C. and stir at this temperature for 66 hrs. Cool the resulting solution to room temperature, and add 3 drops of water. Filter the precipitate wash with ether to give the title compound (279 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[CH:10]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[Br:35][CH2:36][CH2:37]Br>C(#N)C>[CH3:7][O:8][C:9](=[O:34])[CH:10]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:37][CH2:36][Br:35])=[CH:16][CH:17]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a solution of potassium carbonate (2 kg) in acetonitrile (5000 ml) is added 2-((2-benzoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester (555 g, 1.48 mol) and 1,2-dibromoethane (1000 ml). Then the mixture is stirred at room temperature for 24 hours. After that, the reaction mixture is filtered, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give 2-((2-benzoylphenyl)amino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (442 g, 62%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]2[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][CH2:12]2)[OH:10])[CH2:4][CH2:3]1.[CH3:21][O:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([N:29]=[C:30]=[O:31])=[O:28])=[CH:25][CH:24]=1>[Na].C1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([NH:29][C:30]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([CH:11]3[O:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[O:13][CH2:12]3)[OH:10])[CH2:4][CH2:3]2)=[O:31])=[O:28])=[CH:25][CH:24]=1
Reactant: COc1ccc(C(=O)N=C=O)cc1
Reactant: NC1CCN(CC(O)C2COc3ccccc3O2)CC1
Agent: [Na]
Solvent: c1ccccc1
Product: COc1ccc(C(=O)NC(=O)NC2CCN(CC(O)C3COc4ccccc4O3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.3 %

Procedure:
Erythro 4-amino-1-[2-(1,4-benzodioxan-2-yl)-2-hydroxy-ethyl]piperidine (2.0 g 0.0072 m)) was dissolved in sodium dried benzene (100 mls). To the stirring solution was added p-methoxy benzoyl isocyanate (1.27 g 0.0072m) in benzene (20 mls) and the solution stirred at room temperature for 18 hours. The solvent was evaporated and the residue heated with isopropyl alcohol. The insoluble solid was filtered off and triturated with hot ethanol, filtered and dried to give the title compound (0.5 g 15%).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[CH:31](OCC)=[O:32]>>[CH:31]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[O:32]
Reactant: CCOC=O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC=O)c3ccccc32)cc1

Procedure:
A mixture of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) and ethyl formate (10 ml) is refluxed for 4 hours. The reaction solution is concentrated and the resulting residue is recrystallized from ethanol/petroleum ether to give 5-formylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as colorless columnar crystal, m.p. 211-213° C.