Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:19])([CH3:18])[CH2:5][O:6][N:7]1C(=O)C2C(=CC=CC=2)C1=O.[CH3:21][NH2:22]>CO>[NH2:7][O:6][CH2:5][C:4]([CH3:19])([CH3:18])[C:3]([NH:22][CH3:21])=[O:2]
Reactant: CN
Reactant: COC(=O)C(C)(C)CON1C(=O)c2ccccc2C1=O
Solvent: CO
Product: CNC(=O)C(C)(C)CON
Temperature: 60 °C
Reaction time: 13 h

Procedure:
To 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (800 mg) obtained in Step A was added a 40% solution of methylamine in methanol (6 ml), and the mixture was stirred at 60° C. for 13 hours. After the reaction mixture was concentrated under reduced pressure, dichloromethane was added to the residue, and insoluble matter was filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (202 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:4]2[C:3]3[C:8](=[N:9][CH:10]=[CH:11][C:2]=3[NH:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:21][CH:20]=3)[NH:7][C:6](=[O:12])[C:5]=2[CH:13]=1
Reactant: Nc1ccc(NC(=O)c2ccccc2)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccc(Cl)cc12
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4cc(Cl)ccc4c23)cc1)c1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 267 using 1,8-dichloro-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-aminophenyl)benzamide to provide 275. LC-MS (M+H=442, obsd.=442).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:17][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:9])=[O:8])=[O:18]
Reactant: COc1ccccc1CO
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1COC(=O)[C@@H]1CSCCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
0.200 g (0.6 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.138 g (1.0 mmol) of 2-methoxybenzyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:6) to obtain the product as a oil (0.19 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.[CH2:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32](O)=[O:33])=[C:24]1[CH3:35])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]([N:1]2[CH2:6][CH2:5][C:4]3([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[O:7]3)[CH2:3][CH2:2]2)=[O:33])=[C:24]1[CH3:35])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: Cc1c(C(=O)O)c2ccccc2n1Cc1ccccc1
Product: Cc1c(C(=O)N2CCC3(CC2)OC(=O)c2ccccc23)c2ccccc2n1Cc1ccccc1

Procedure:
Following the general procedure I as described above, the acylation of 3H-spiro[2-benzofuran-1,4′-piperidin]-3-one prepared as described in example 16 above with 1-benzyl-2-methyl-1H-indole-3-carboxylic acid (preparation described in example 1), gave the title compound. ES-MS m/e (%): 451.6(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[OH:11].[N:13]#[C:14]Br.C(O)C>O>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:11][C:14]([NH2:13])=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: N#CBr
Solvent: CCO
Solvent: O
Product: COC(=O)c1cccc2nc(N)oc12
Yield: 76 %

Procedure:
A mixture of 913 mg (5.46 mmol) 3-amino-2-hydroxy-benzoic acid methyl ester, 894 mg (8.19 mmol) of cyanogen bromide, 14.4 mL of ethanol and 1.6 mL of water was heated under reflux for 1 h. Ethanol was evaporated under reduced pressure and 20 mL of 2 N aq. Na2CO3 was added to the residue. The precipitated solid was filtered and washed with water. The remaining product was treated with methanol and the soluble filtrate containing the product was evaporated in vacuo to provide 797 mg (4.15 mmol, 76%) of 2-amino-benzooxazole-7-carboxylic acid methyl ester. LCMS: 193 (M+1)+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]([C:14]([O:16]CC)=O)=[CH:7]2.[CH3:19][N:20]1C2C(=CC=CC=2)C=C1C(OCC)=O>>[CH3:19][NH:20][C:14]([C:8]1[N:9]([CH3:13])[C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([F:3])=[CH:12][CH:11]=2)=[O:16]
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1C
Reactant: CCOC(=O)c1cc2ccccc2n1C
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)c1cc2cc(F)ccc2n1C
Yield: 68 %

Procedure:
According to the procedure of Preparation 1 (b), except substituting ethyl 5-fluoro-1-methyl-1H-indole-2-carboxylate for the ethyl 1-methyl-1H-indole-2-carboxy late, the title compound (2.1 g, 68%) was prepared as a white solid: MS (ES) m/e 207 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][NH:13][C:14]=2[NH2:15])=[CH:6][CH:5]=1.CN(C)[CH:21]=[CH:22][C:23](=O)[CH3:24].C(O)(=O)C>C(O)C>[CH3:24][C:23]1[CH:22]=[CH:21][N:13]2[N:12]=[C:11]([NH2:16])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)=[C:14]2[N:15]=1
Reactant: Nc1n[nH]c(N)c1-c1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)C=CN(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccn2nc(N)c(-c3ccc(OC(F)(F)F)cc3)c2n1
Temperature: -10 °C

Procedure:
The product from Example 1B (200 mg, 0.775 mmol) was charged to a microwave vial with a stir bar. A solution of 4-(dimethylamino)but-3-en-2-one (175 mg, 1.55 mmol) in ethanol (2 mL) was added, and the mixture was stirred at room temperature as acetic acid (25 ΞL, 0.437 mmol) was added. The solution was irradiated in the microwave at 150° C. for 35 minutes, then cooled to room temperature and finally to −10° C. The precipitate was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluted with hexanes-EtOAc, 70:30-40:60) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.47 (s, 3H), 5.71 (s, 2H), 6.69 (d, J=7.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.87-7.98 (m, 2H), 8.62 (d, J=7.1 Hz, 1H).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH2:20][OH:21].[C:22](=O)(O)[O-].[Na+]>CO>[OH:21][NH:20][C:8](=[NH:9])[C:7]1[CH:2]=[CH:3][C:4]([CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[C:5]([CH3:22])[CH:6]=1
Reactant: NO
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1C#N
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=N)NO)ccc1CCC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 58.1 %

Procedure:
A mixture of 2.5 g (10.2 mmol) of tert-butyl 3-(3-methyl-4-cyanophenyl) propionate (from Step B), 0.85 g (12.2 mmol) of hydroxylamine hydrochloride and 2.57 g (30.6 mmol) of sodium bicarbonate in 30 mL of methanol was heated in a sealed tube at 100° C. for 16 h. The reaction mixture was cooled to rt, then concentrated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was separated and washed with sat'd NaCl (3×50 mL), dried over MgSO4, and concentrated. Chromatography on a Biotage 40M cartridge using 7:3 v/v hexanes/EtOAc as the eluant afforded 1.65 g (58%) of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.45 (s, 9H), 2.40 (s, 3H), 2.54 (t, J=7.8, 2H), 2.90 (t, J=7.8, 2H), 5.05 (s, 2H), 7.04 (d, J=7.8, 1H), 7.08 (s, 1H), 7.27 (d, J=7.8, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[N:25][OH:26])[CH2:9][N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCN(CC=C)CC(=O)c1cccc(Br)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C=CCN(CC=C)CC(=NO)c1cccc(Br)c1
Temperature: 50 °C
Yield: 119.3 %

Procedure:
A solution of 1-(3-bromophenyl)-2-(diallylamino)ethanone (60 g, 204.7 mmol) in ethanol (720 mL) and pyridine (24.8 mL, 307 mmol) is stirred 15 minutes at 22° C. Hydroxylamine hydrochloride (17 g, 246 mmol) is added in portions to the solution over 1 hour. The reaction is warmed to 50° C. for 2 hours and then heated to 70° C. for 16 hours. The solvent is evaporated and the residue partitioned in water (300 mL) and methyl tert-butyl ether (300 mL). The organic layer is separated and washed with water (100 mL, 2×) and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated to dryness to give the title compound (75.5 g, 79%). ES/MS (m/e): 309 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Br:27]Br.C(O)(=O)C>C(Cl)(Cl)Cl>[Br:27][CH:10]([C:11](=[O:16])[C:12]([CH3:14])([CH3:13])[CH3:15])[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)C(CC(=O)C(C)(C)C)c2ccc(Cl)cc2Cl)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)C(c2ccc(Cl)cc2Cl)C(Br)C(=O)C(C)(C)C)cc1

Procedure:
The bromination of 1-(2,4-dichlorophenyl)-1-p-toluenesulfonyl-4,4-dimethylpentan-3-one was carried out in the same manner as that of Example 3 but using 25 g of 1-(2,4-dichlorophenyl)-1-p-toluenesulfonyl-4,4-dimethyl-3-one, 9.2 g of bromine, 200 ml of acetic acid and 300 ml of chloroform, and 29 g of 2-bromo-1-(2,4-dichlorophenyl)-4,4-dimethyl-1-p-toluenesulfonylpentan-3-one was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH:14][NH:15]C(OC(C)(C)C)=O)[CH3:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)[Cl:31].C([SiH](C(C)C)C(C)C)(C)C>>[Cl-:31].[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH2+:14][NH2:15])[CH3:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: ClCCl
Reactant: CCOC(=O)c1ccc(C(C)NNC(=O)OC(C)(C)C)cc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(C(C)[NH2+]N)cc1
Product: [Cl-]

Procedure:
tert-Butyl 2-{1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinecarboxylate (29 g, 94 mmol) was treated with 100 ml of TFA-DCM-triisopropylsilane (20:20:1) at room temperature for one hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in water (100 ml), washed with DCM 2×. The DCM was back extracted with water 3×. HCl (5N, 20 ml) was added to the combined water solution and concentrated to ˜50 ml. CH3CN (50 ml) was added and this was lyophilized to yield {1-[4-(ethoxycarbonyl)phenyl]ethyl}-hydrazinium chloride. NMR (500 MHz, acetone-d6) δ: 1.34 (t, J=7.1 Hz, 3H); 1.67 (d, J=6.8 Hz, 3H); 4.33 (q, J=7.1 Hz, 2H), 4.97 (q, J=6.8 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.97 (d, J=8.5 Hz, 2H). MS C11H16N2O2 Cald: 208.12; Obsd (M+1): 209.19.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[I-].[Na+].[OH-].[Na+].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(CC)(C)C.C1(C)C=CC=CC=1>[CH2:10]([N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:10]([N:2]1[N:3]=[CH:4][CH:5]=[N:1]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1c[nH]nn1
Reactant: ClCc1ccccc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCC(C)(C)O
Product: c1ccc(Cn2ccnn2)cc1
Product: c1ccc(Cn2nccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
1,2,3-Triazole (1523 mg, 22.05 mmol), sodium iodide (2203 mg, 14.7 mmol) and sodium hydroxide (882 mg, 22.05 mmol) were added to t-amyl alcohol (5.8 ml), and the mixture was refluxed under stirring for 1 hour. Benzyl chloride (1861 mg, 14.7 mmol) was dissolved in t-amyl alcohol (5.8 ml) and added dropwise under reflux over 1 hour. The mixture was refluxed under stirring for 1 hour. The mixture was cooled to room temperature and toluene (50 ml) was added. The mixture was washed with water (50×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/3) to give 1-benzyl-1H-1,2,3-triazole (2.10 g) as white crystals, yield 90%, and 2-benzyl-2H-1,2,3-triazole (140 mg) as white crystals (yield 6%). 1-benzyl-1H-1,2,3-triazole
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=NN=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][C@@H:18]([N:20]([C:25]([C:27]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:30]3[CH:38]=[CH:39][CH:40]=[CH:41][C:29]=3[N:28]=2)=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:17][C@@H:16]([C:42](O)=[O:43])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C1CCC(N=C=NC2CCCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:30]2[CH:38]=[CH:39][CH:40]=[CH:41][C:29]=2[N:28]=[C:27]1[C:25]([N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C@H:18]1[CH2:17][C@@H:16]([C:42]2[O:43][C:2]([CH3:1])=[N:6][N:5]=2)[CH2:15][N:14]([C:12]([O:11][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:13])[CH2:19]1)=[O:26]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: Cc1nnn[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nnc(C)o3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
Methyltetrazole (63 mg) and (3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (265 mg) were dissolved in toluene (5 ml), DCC (155 mg) was added and the mixture was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, filtered and the solvent of the mother liquor was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (100 mg).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=1)[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17].CCN(C(C)C)C(C)C>C(#N)C>[CH2:19]([O:18][C:16]([C:15]1[CH:14]=[C:13]([NH:12][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])[CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:20]=[CH2:21]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: C=CCOC(=O)c1cccc(N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)c1cccc(NC(C(=O)O)c2ccccc2)c1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
2-Bromo-2-phenylacetic acid (1.86 g, 8.65 mmol) was added to a solution of allyl 3-aminobenzoate (2.30 g, 13.0 mmol) and DIPEA (2.27 ml, 13.0 mmol) in acetonitrile (48 ml). The reaction was heated at 100° C. for 1 hour under microwave irradiation. The solvent was removed in vacuo and the residue was purified by flash chromatography (DCM/MeOH=95/5) to obtain 2-(3-(allyloxycarbonyl)phenylamino)-2-phenylacetic acid (2.65 g, 98% yield).
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[NH:35]1[C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[C:37]([CH:44]=O)=[CH:36]1>N1C=CC=CC=1>[CH:1]([N:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[C:15](=[CH:44][C:37]2[C:38]3[C:39](=[N:40][CH:41]=[CH:42][CH:43]=3)[NH:35][CH:36]=2)[C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2]
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: c1ccncc1
Product: CC(C)N(C(=O)CN1C(=O)C(=Cc2c[nH]c3ncccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Yield: 47.1 %

Procedure:
Following the procedure described for Example 1(A), Step A, N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide (Preparation 7(A)) (500 mg, 1.10 mmol) was condensed with 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (160 mg, 1.16 mmol) in pyridine (5 mL). Purification by medium pressure chromatography eluting with a solvent gradient (5% acetone in CH2Cl2 to 50% acetone in CH2Cl2 to 10% MeOH in CH2Cl2) yielded 300 mg of N-isopropyl-2-[5-oxo-1-phenyl-4-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-phenyl-acetamide. 1H NMR (CDCl3) δ 8.31 (d, 1H), 8.05 (d) and 7.96 (d, total HK), 7.71 (m, 1H), 7.59 (m, 2H), 7.33-7.51 (m, 9H), 7.17 (m, 2H), 7.01 (m, 1H), 6.80 (t, 1H), 5.09 (m, 1H), 4.50 (d) and 4.30 (d, total 1H), 4.15 (m, 1H), 3.92 (d, 1H), 1.14 (m, 6H); MS 580.6 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.C(OCC)(=O)C>CN(C=O)C.O>[C:10]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([CH2:7][CH2:8][O:9][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19])[N:5]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)c1cc(N)n(CCO)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(N)n(CCO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To 2-(5-amino-3-tert-butyl-pyrazol-1-yl)-ethanol (3.42 g, 0.019 mol), add TBDMSCl (3.38 g, 1.2 equiv.) and imidazole (3.18 g, 2.5 equiv.) in DMF (7 mL) and stir overnight at room temperature under N2. Dilute the reaction with ethyl acetate and water. Wash the organic layer with water then saturated aqueous saturated sodium chloride and then dry over magnesium sulfate, filter, and concentrate in vacuo to give a solid (5.5 g, 99%) which is used without further purification. MS (ES), m/z 298 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:19])[C:8]([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[N:9]2)=[CH:4][C:3]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23]>C(O)=O>[ClH:1].[OH:19][C:7]1[C:8]([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:2][CH:11]=2
Reactant: O=C(O)CNC(=O)c1nc2cc(Cl)c(OCC(F)(F)F)cc2cc1O
Solvent: O=CO
Product: Cl
Product: O=C(O)CNC(=O)c1nc2ccc(OCC(F)(F)F)cc2cc1O

Procedure:
0.5 g (1.3 mmol) of N-((7-chloro-3-hydroxy-6-(2,2,2-trifluoroethyloxy)quinolin-2-yl)carbonyl)glycine (title compound from Example 31) was dissolved in 26 ml of methanolic formic acid (4.4% strength), and a further 26 ml of methanolic formic acid were added at 20° C. After addition of 0.5 g of Pd/C (10%), the mixture was stirred at 20° C. for 1 hour, the catalyst was filtered off, the filtrate was concentrated and the residue was crystallized with diisopropyl ether. 250 mg of product were obtained, melting point>300° C. (sintering at 207° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl.O>C(O)C>[ClH:27].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=3[C:10](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[CH2:9]2)[CH:7]=1
Reactant: N=C(N)NN
Reactant: Cc1cc(C)c2c(n1)CC(c1cc(F)ccc1C)CC2=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(n1)CC(c1cc(F)ccc1C)CC2=NNC(=N)N
Yield: 85.7 %

Procedure:
A solution of 7-(5-fluoro-2-methylphenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.52 g) in ethanol (30 ml) was combined with concentrated hydrochloric acid (1.0 ml) and water (1.0 ml), and the mixture was heated under reflux for 12 hours. The mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to obtain 7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-2,4-dimethyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound L) (1.25 g) as a colorless crystal.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1([C:8](OC)=[O:9])[CH2:7][CH2:6]1.[C:14](#[N:16])[CH3:15]>C1COCC1>[O:9]=[C:8]([C:5]1([C:4]([F:13])([F:12])[F:3])[CH2:7][CH2:6]1)[CH2:15][C:14]#[N:16]
Reactant: CC#N
Reactant: COC(=O)C1(C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1(C(F)(F)F)CC1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
To a slurry of NaH (432 mg, 18 mmol) in THF (40 mL) heated at reflux was added dropwise over 10 minutes a solution of methyl 1-(trifluoromethyl)cyclopropanecarboxylate (2.0 g, 11.9 mmol) in acetonitrile (940 uL, 12 mmol) and the mixture heated at reflux overnight. After cooling to room temperature, the reaction was partitioned between ether and H2O, the aqueous layer acidified with 1N HCl(aq), extracted with ether, and the combined org layers washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (5-40% EtOAc/hexanes) to give 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (1.04 g, 5.88 mmol, 49%). LC-MS (ESI) m/z 178 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:3]1.[C:13]1([CH2:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S1C=CC=C1.[H][H]>C(O)C.[Pd].CO>[CH3:1][CH:2]1[CH:7]([NH:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:3]1
Reactant: NCc1ccccc1
Reactant: [H][H]
Reactant: COC(=O)N1CCC(=O)C(C)C1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: c1ccsc1
Product: COC(=O)N1CCC(NCc2ccccc2)C(C)C1

Procedure:
A mixture of 26 parts of methyl 3-methyl-4-oxo-1-piperidinecarboxylate, 16.5 parts of benzenemethanamine, 2 parts of a solution of thiophene in ethanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dry, yielding 40.2 parts of methyl 3-methyl-4-[(phenylmethyl)amino]-1-piperidinecarboxylate as a residue (interm. 26).