Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=2[CH3:34])[CH2:24][CH2:23]1>>[C:36]([NH:35][C:30]1[CH:31]=[CH:32][C:33]([CH3:34])=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:29]=1)(=[O:40])[CH:37]([CH3:39])[CH3:38]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(C)(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 96 was prepared from 2,2-diphenyl propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methyl phenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.37–7.23 (m, 13H), 7.08 (d, 1H, J=8.8 Hz), 6.14 (t, 1H, J=5.6 Hz), 3.37 (dd, 2H, J=6.4, 12.0 Hz), 2.90 (d, 2H, J=11.6 Hz), 2.63 (m, 1H), 2.49 (m, 1H), 2.31 (t, 2H, J=6.8 Hz), 2.27 (s, 3H), 2.02 (s, 3H), 1.99–1.94 (m, 2H), 1.71–1.59 (m, 6H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 526.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9](=[CH:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)[C:10](O)=[O:11].[CH:23]1([N:29]=[C:30]=NC2CCCCC2)CCCCC1.CNC>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9](=[CH:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)[C:10]([N:29]([CH3:30])[CH3:23])=[O:11]
Reactant: O=C(O)C(=CNc1ccc(I)cc1)C(=O)c1ccccc1Cl
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)C(=CNc1ccc(I)cc1)C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a suspension of 2-chloro-α-[[(4-iodophenyl)amino]methylene]-β-oxobenzenepropanoic acid (43 mg, 0.10 mmol) in 1 mL of CH2Cl2 was added N,N′-dicyclohexylcarbodiimide (21 mg, 0.10 mmol). The mixture was cooled in an ice bath and 50 μL (0.10 mmol) of a 2M solution of dimethylamine in THF was added. The reaction mixture was stirred at rt for 16 h. The formed DCU was removed by filtration. The filtrate was washed with water and evaporated to dryness. The title compound (22 mg, 50%) was isolated by column chromatography (5% MeOH in CH2Cl2); MS 410 (M−45), 455(M+1), 477(M+Na+).
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[Br:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1N.NC1C=CC=CC=1>CC#N>[CH2:3]([C:14]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:13]=1[Br:12])[CH:1]=[CH2:2]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: CC(C)(C)ON=O
Solvent: Nc1ccccc1
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCc1cc([N+](=O)[O-])ccc1Br
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 2-bromo-5-nitroaniline (651 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 35-40° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 23° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 49:1) gave 568 mg (78%) allyl-2-bromo-5-nitrobenzene as a light yellow oil containing 7% of 3,4-dibromo-nitrobenzene, which crystallized upon standing overnight in the refrigerator. This corresponds to 72% yield of allyl-2-bromo-5-nitrobenzene. The allyl-2-bromo-5-nitrobenzene could be purified by crystallization from pentane. 1H NMR (CDCl3, 400 MHz) δ 8.10, (d, 1H, J=2.7 Hz), 7.95, (dd, 1H, J=8.7, 2.7 Hz), 7.74, (d, 1H, J=8.7 Hz), 6.03-5.92, (m, 1H), 5.26-5.13, (m, 2H), 3.60, (m, 2H, J=6.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 147.7, 142.0, 134.1, 134.1, 132.3, 125.3, 122.9, 118.8, 40.5; Anal HRMS Calcd. for C9H8BrNO2 (M): 240.9738. Found: 240.9739.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])C.C1(C)C=CC=CC=1.CCOCC.[CH2:30]([NH:32][CH2:33][CH2:34][NH2:35])[CH3:31]>C(OCC)(=O)C>[CH2:30]([NH:32][CH2:33][CH2:34][NH:35][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:31]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCNCCN
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCNCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reaction time: 8 h
Yield: 82 %

Procedure:
A fine powder of 5-nitro-2-indolecarboxylic acid ethyl ester (0.8 g, 3.41 mmol) was suspended in 2 ml of N-ethylethylenediamine under argon and the reaction mixture was stood at 55° C. overnight. The mixture was co-evaporated with toluene to dryness. The brown solid obtained was dissolved in 6 ml of ethyl acetate and 40 ml of ether was added to precipitate the product. After centrifugation, the liquid was poured out and the solid was washed with 30 ml of ether and dried to give small brown crystals (0.77 g, 82%). ESI MS: 277.11 (M+H+), 299.09 (M+Na+). 1H NMR (DMSO-d6) δ8.67 (d, 1H), 8.04 (dd, 1H), 7.55 (d, 1H), 7.37 (s), 3.36 (m, 3H), 2.69 (q, 2H), 2.55 (q, 2H), 0.99 (t, 3H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[CH:30]=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:33]1C=CC(F)=CC=1C(=O)C>>[C:30]([C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:8]1[NH:9][C:10]2[C:15]([C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[CH:14][CH:13]=[C:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH:11]=2)(=[O:31])[CH3:33]
Reactant: CC(=O)c1cc(F)ccc1Br
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(F)cc3C=O)[nH]c2c1
Product: CC(=O)c1cc(F)ccc1-c1[nH]c2cc(C(=O)OC(C)(C)C)ccc2c1C1CCCCC1
Yield: 65 %

Procedure:
The title product tert-butyl 2-(2-acetyl-4-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate 33c was synthesized following the procedure reported for the synthesis of tert-butyl 3-cyclohexyl-2-(4-fluoro-2-formylphenyl)-1H-indole-6-carboxylate 32d, using 1-(2-bromo-5-fluorophenyl)ethanone 33b instead of 2-bromo-5-fluorobenzaldehyde 32c, and was obtained in 65% yield as a white solid; m/z 436 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[N+:11]([O-:14])([OH:13])=[O:12].[NH2:15][NH:16][C:17]([NH:19][NH2:20])=[NH:18].[N+]([O-])(O)=O>C(O)C.O>[N+:11]([O-:14])([OH:13])=[O:12].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[N:15][NH:16][C:17]([NH:19][N:20]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)=[NH:18]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: N=C(NN)NN
Solvent: CCO
Solvent: O
Solvent: O=[N+]([O-])O
Product: N=C(NN=Cc1ccc(Cl)c(Cl)c1)NN=Cc1ccc(Cl)c(Cl)c1

Procedure:
A boiling solution of 17.6 grams of 3,4-dichlorobenzaldehyde in 250 milliliters of ethanol is stirred vigorously as a solution of 6.1 grams of 1,3-diaminoguanidine nitrate and 0.5 milliliters of concentrated nitric acid in 50 milliliters of water is added in one portion. The reaction mixture is stirred as the temperature recedes to room temperature. The reaction mixture is then allowed to stand for several hours. The precipitate which forms is collected, washed with hot ethanol, air dried and finally dried at 60°C. under reduced pressure. The yield is 17.5 grams of product and the melting point is 195°-196°C. with decomposition.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[O:14])[C:5]1=[O:36])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[Cl:44]CCl>>[ClH:44].[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]3([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:21][CH2:22]2)=[O:14])[C:5]1=[O:36])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCN(C3(C(=O)OC(C)(C)C)CCCCC3)CC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(C3(C(=O)O)CCCCC3)CC2)c2ccccc21
Product: Cl
Reaction time: 12 h

Procedure:
To a stirred solution of tert-butyl 1-[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]cyclohexanecarboxylate (400 mg, 0.802 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL, 65.2 mmol) at room temperature. After 12 h, the volatile components were removed under reduced pressure. To the residue was added 4N HCl in dioxane (5.0 mL) was added and stirred for 10 min. Then, the volatile was removed under reduced pressure.
Reaction SMILES: [CH2:1]([C@H:4]([C@H:8]([OH:10])[CH3:9])[C:5]([OH:7])=O)[C:2]#[CH:3].[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][NH2:18].C(Cl)CCl>ClCCl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][NH:18][C:5](=[O:7])[C@H:4]([CH2:1][C:2]#[CH:3])[C@H:8]([OH:10])[CH3:9]
Reactant: NOC1CCCCO1
Reactant: C#CC[C@@H](C(=O)O)[C@@H](C)O
Solvent: ClCCCl
Solvent: ClCCl
Product: C#CC[C@@H](C(=O)NOC1CCCCO1)[C@@H](C)O
Temperature: 23 °C
Reaction time: 4 h
Yield: 37.3 %

Procedure:
To a solution of (2R,3R)-2-(2-propyne-1-yl)-3-hydroxybutanoic acid (3.0 g, 21.13 mmol) in dichloromethane (50 mL) is added 2-tetrahydropyranyloxyamine (3.0 g, 25.35 mmol) and EDC (4.5 g, 23.24 mmol). The resulting solution is stirred at 23° C. for 4 h, then diluted with dichloromethane (100 mL) and washed with 1 M hydrochloric acid. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(2-propyne-1-yl)-3-hydroxybutanoic acid 2-tetrahydropyranyloxyamide as a foam (1.9 g, 37% yield). 1H NMR (400 MHz, CDCl3) δ8.82 (bs, 1H), 4.96 (m, 1H), 3.94 (m, 2H), 3.62 (m, 1H), 2.64 (m, 1H), 2.56 (m, 1H), 2.23 (m, 1H), 2.04 (m, 1H), 1.82 (m, 2H), 1.61 (m, 4H), 1.23 (d, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:40]1([CH2:46][NH2:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:47][CH2:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)NCc4ccccc4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.5 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added 1-phenylmethanamine (47 mg, 0.44 mmol), and the mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (190 mg) as a yellow solid. LC-MS (ES) m/z=431 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[CH3:11])=[CH:4][CH:3]=1.ClC(C)[CH2:23][NH:24]C1C=CC(Cl)=CC=1.CC1C=CC=C(C)C=1N.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH:10]([CH3:11])[N:12]([C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[C:23]2=[NH:24])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1NC(C)CNc1ccc(Cl)cc1
Reactant: CC(Cl)CNc1ccc(Cl)cc1
Agent: Cc1cccc(C)c1N
Agent: Cl
Product: Cc1cccc(C)c1N1C(=N)N(c2ccc(Cl)cc2)CC1C
Yield: 50.9 %

Procedure:
1-(4'-Chlorophenyl-amino)-2-(2',6'-dimethylphenylamino)-propane, applied as starting substance, is obtained with a yield of 50.9% by reacting N-(β-chloropropyl)-4-chloro-aniline, a compound prepared as described in Example 27, point (b), with 2,6-dimethylaniline according to the method given in Example 25, point (a). The hydrochloride of the product melts at 170°-178° C.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[F:25][C:26]1[CH:27]=[C:28]([NH:32][NH2:33])[CH:29]=[CH:30][CH:31]=1>>[F:25][C:26]1[CH:27]=[C:28]([N:32]2[C:2]3[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=3)[C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: NNc1cccc(F)c1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3cccc(F)c3)c3cc(O)ccc23)c(O)c1
Yield: 3.2 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.400 g, 1.60 mmol), sodium acetate (0.267 g, 3.3 mmol) and 3-fluorophenylhydrazine hydrochloride (0.400 g, 2.5 mmol) to give 0.017 g of product as a pink solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:22])=O>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:10]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)Cl
Reaction time: 3 h
Yield: 70.5 %

Procedure:
2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (1.2 g, 46.0 mmol) was placed into 40 ml scintillation vial equipped with a small stir bar. 10.0 ml of anhydrous chloroform was added following by 1.8 ml of thionyl chloride and 2 drops of anhydrous DMF. After 3 hours, the solvent and excess thionyl chloride were evaporated under vacuum. The brown residue was treated with 40 ml of hexane, filtered, and concentrated to give 985 mg (Yield=70.5%) of the product as a greenish oil. 1H NMR (CDCl3, 400 MHz) δ 8.15 (d, 1H), 7.95 (d, 1H), 7.3 (t, 1H), 2.75 (s, 3H), 1.4 (s, 12H). The reaction was run several times and the yield was ranging from 60 to 99%.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([O:19][CH3:20])=[N:12][CH:13]=[C:14]([CH:18]=2)[C:15]([OH:17])=O)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Cl.C[O:23][C:24]([C:26]1([NH2:35])[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25]>>[CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:14]([C:15]([NH:35][C:26]3([C:24]([OH:25])=[O:23])[CH2:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:34]3)=[O:17])[CH:13]=[N:12][C:11]=2[O:19][CH3:20])[CH:7]=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COc1ncc(C(=O)O)cc1-c1cccc(C(C)C)c1
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Agent: Cl
Product: COc1ncc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1-c1cccc(C(C)C)c1

Procedure:
The compound of step 2 was reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 2 of example 13, and the obtained ester hydrolyzed in analogy to example 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:27][CH3:28])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19]C(OC(C)(C)C)=O)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cu](C#N)[C:30]#[N:31].O.N>CN(C)C=O>[C:30]([C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:27][CH3:28])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1)#[N:31]
Reactant: N#C[Cu]C#N
Reactant: CCc1nc(-c2cccc(Br)c2)c(-c2ccnc(NC(=O)OC(C)(C)C)c2)s1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(-c2cccc(C#N)c2)c(-c2ccnc(N)c2)s1
Temperature: 150 °C
Reaction time: 20 h
Yield: 56.4 %

Procedure:
To a solution of 4-(3-bromophenyl)-5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-1,3-thiazole (0.5 g, 1.1 mmol) in N,N-dimethylformamide (10 mL) was added copper cyanide (0.25 g, 1.6 mmol), and the mixture was stirred for 20 hours at 150° C. under argon atmosphere. Into the reaction mixture was poured ammonia water, and the deposit was removed, then, extracted with ethyl acetate. The extracts were washed with water, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) to obtain a crystal. This crystal was washed with hexane-ethyl acetate to obtain a title compound (0.19 g, yield 57%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:14]([C:20]5[CH:25]=[CH:24][C:23]([C:26]6([N:31]7C(=O)C8C(=CC=CC=8)C7=O)[CH2:29][C:28](=[O:30])[CH2:27]6)=[CH:22][CH:21]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1.[C:48](O)(C(F)(F)F)=[O:49].O.NN.[CH3:58]O>>[CH3:58][O:30][C:28]1([O:49][CH3:48])[CH2:29][C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:14]3[C:13]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:12][C:11]4[C:10]5=[N:9][N:8]=[C:7]([C:5]6[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=6)[N:19]5[CH:18]=[CH:17][C:16]=4[N:15]=3)=[CH:21][CH:22]=2)([NH2:31])[CH2:27]1
Reactant: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(N7C(=O)c8ccccc8C7=O)CC(=O)C6)cc5)nc4ccn23)c1
Reactant: CO
Reactant: O=C(O)C(F)(F)F
Agent: NN
Solvent: O
Product: COC1(OC)CC(N)(c2ccc(-c3nc4ccn5c(-c6cn(C)cn6)nnc5c4cc3-c3ccccc3)cc2)C1
Temperature: 100 °C

Procedure:
To a micro reactor vessel was added (2-(1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}-3-oxocyclobutyl)-1H-isoindole-1,3(2H)-dione (1-13) (100 mg, 0.162 mmol), TFA (1 mL), and MeOH (5 mL), and the mixture was heated under microwave irradiation at 100° C. for 10 minutes. Then hydrazine hydrate (80 mg, 1.6 mmol) was added, and the mixture was heated under microwave irradiation at 100° C. for 10 minutes. The solvent was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were free based by suspending in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 3,3-dimethoxy-1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine (1-18). HRMS (M+H)+: observed=532.2461, calculated=532.2466.
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Br[CH2:46][CH:47]1[CH2:49][CH2:48]1.CC[CH2:52][CH2:53][CH2:54][CH3:55]>CN(C=O)C>[CH:49]1([CH2:48][N:23]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][N:19]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:18]/[CH:17]=[CH:16]/[CH2:15][N:14]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:13][CH2:12][CH2:11][N:10]([CH2:52][CH:53]2[CH2:55][CH2:54]2)[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[CH2:47][CH2:46]1
Reactant: BrCC1CC1
Reactant: CCCCCC
Reactant: CC(C)(C)OC(=O)NCCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C/C=C/CN(CCCN(CC1CC1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCN(CC1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.4 g (10 mmol) of sodium hydride dispersion (approx. 60%) is added, with stirring, to a solution of 1.5 g (2.5 mmol) of (E)-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene in 21.5 ml of DMF. The mixture is stirred for 15 min. at room temperature; then 1.06 ml (10 mmol) of bromomethyl-cyclopropane (approx. 90% ) are added to the reaction mixture and stirring is continued for 90 h at room temperature. Working up analogously to Example 1a) yields the title compound in the form of a colourless resin, Rf value=0.47 (silica gel/ethyl acetate:hexane (2:3)).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[PH2:25]([O-:27])=[O:26].[Na+]>O>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[PH:25](=[O:26])[OH:27])([O-:13])=[O:12]
Reactant: O=[PH2][O-]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[PH](=O)O

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (1.8 g, 4.97 mmol), sodium hypophosphite (0.88 g, 9.94 mmol) and cupric sulfate (180 mg) in 20 ml of methyl nitrile/water (4:1) is heated under reflux for 24 hours. The reaction is poured into water, extracted with methylene chloride, dired and chromatographed (silica gel, eluting with 10% methanol/chloroform) to yield 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Br:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].O>ClCCl>[Br:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:8](=[O:10])[CH3:9]
Reactant: Nc1cccc(F)c1Br
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(F)c1Br
Reaction time: 72 h

Procedure:
2.7 ml of triethylamine and then 1.2 ml of acetyl chloride are added to a solution of 3 g of 2-bromo-3-fluoroaniline in 30 ml of dichloromethane. The reaction mixture is stirred for 72 hours and then treated with a mixture of water and dichloromethane. The phases are separated and the organic phase is concentrated so as to give 3.75 g of N-(2-bromo-3-fluorophenyl)acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[OH:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[C:20](=[O:26])[NH:21][CH2:22][C:23]([OH:25])=O.[C:31]([O-])(=[O:33])[CH3:32].[Na+]>C(OC(=O)C)(=O)C>[C:31]([O:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[C:20]1[O:26][C:23](=[O:25])/[C:22](=[CH:9]/[C:8]2[CH:11]=[CH:12][C:5]([O:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[Br:1])=[CH:6][CH:7]=2)/[N:21]=1)(=[O:33])[CH3:32]
Reactant: O=Cc1ccc(Oc2ccccc2Br)cc1
Reactant: O=C(O)CNC(=O)c1ccccc1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccccc1C1=N/C(=C\c2ccc(Oc3ccccc3Br)cc2)C(=O)O1
Temperature: 60 °C
Yield: 87.1 %

Procedure:
A suspension of 4-(2-bromophenoxy)benzaldehyde (0.35 g, 1.26 mmol), 2-hydroxy hippuric acid (0.22 g, 1.14 mmol) and sodium acetate (0.12 g, 1.48 mmol) in acetic anhydride (1 mL) is heated to 60° C. on an orbital shaker for one hour and is then cooled to 0° C. The reaction mixture is then concentrated under reduced pressure at 45° C. to afford a crude yellow solid. This solid is washed with ice water (150 mL) and heptane (100 mL) and then dried under vacuum at 40° C. to provide 0.475 g of 2-{(4Z)-4-[4-(2-bromophenoxy)benzylidene]-5-oxo-4,5-dihydro-1,3-oxazol-2-yl}phenyl acetate.