Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[O:30][CH3:31])[C:14]=2[CH:32]=1>ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[O:30][CH3:31])[C:14]=2[CH:32]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(CN2CCOc3ccc(N)cc32)c(OC)c1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2c(c1)N(Cc1ccc(C(=O)OC)cc1OC)CCO2
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Hexanoyl chloride (0.084 g.) was added to a stirred solution of methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)-3-methoxybenzoate (L) (0.2 g.) in dichloromethane (20 ml.), under an atmosphere of nitrogen. The mixture was stirred for one hour and then diluted with dichloromethane (40 ml.). This mixture was washed with water, dried (MgSO4) and evaporated. The residual oil was dissolved in 3:7 v/v ethyl acetate:hexane, and the solution obtained was allowed to filter through a short column of silica gel, washing with one column volume of the same solvent mixture. Evaporation of the column eluate gave the title compound (0.212 g., 82%), as a foam; NMR (250 MHz, CDCl3): 0.9(t,3H, CH2CH3), 1.3(m,4H, CH3.CH2.CH2), 1.6(m,2H, CH2.CH2.CON), 2.2(t,2H, CH2.CON), 3.35(t,2H, OCH2.CH2N), 3.9(br s,6H, OCH3 +CO.OCH3), 4.2(t,2H, OCH2.CH2N), 4.5(s,2H, CH2 --Ar), 6.8(m,3H), 6.9(br s,1H, NH), 7.2(m,1H), 7.5(m, 2H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](O)(=O)[CH2:11]C>O>[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH2:10][CH3:11]
Reactant: CCC(=O)O
Reactant: O=C(O)c1ccccc1
Solvent: O
Product: CCC(=O)c1ccccc1

Procedure:
A mixture of 16 g/h of benzoic acid, 57 g/h of propionic acid and 14.5 g/h of water was evaporated in an evaporator and passed, together with 10 l/h of nitrogen, at 400° C., over 100 ml of a catalyst which contained 2.5% by weight of sodium oxide, the remainder being anatase. The reaction gases were then cooled and were collected in a receiver. From the discharged two-phase mixture, the organic phase was analyzed by gas chromatography. The conversion of both carboxylic acids was 100%. The selectivity with respect to propiophenone was 99%.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[N:23]1[CH:32]=[C:26]2[C:27]([NH2:31])=[N:28][CH:29]=[CH:30][C:25]2=[N:24]1>C(Cl)Cl>[CH3:14][O:13][C:11](=[O:12])[NH:31][C:27]1[C:26]2=[CH:32][N:23]([C:17]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])[N:24]=[C:25]2[CH:30]=[CH:29][N:28]=1
Reactant: Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12
Temperature: 25 °C
Yield: 49.4 %

Procedure:
DIPEA (51 μL, 0.3 mmol) and then methyl chloroformate (19 μL, 0.25 mmol) were added to a solution of 2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-ylamine (60 mg, 0.21 mmol) in DCM (2 mL). The reaction was stirred at room temperature until completion as determined by TLC. The mixture was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (40-50% ethyl acetate in cyclohexane) to afford the title compound as a white solid (35 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.54 (d, J=0.9 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.86 (d, J=1.4 Hz, 1H), 7.84 (d, J=0.6 Hz, 1H), 7.80-7.78 (m, 1H), 7.72 (dd, J=7.3, 0.9 Hz, 1H), 3.97 (s, 3H). LCMS (Method B): RT=2.71 min, m/z: 337 [M+H+].
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[N:16]1([C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][O:25]2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:19]3[CH2:20][CH2:21][N:16]([C:22]([CH:24]4[CH2:28][CH2:27][CH2:26][O:25]4)=[O:23])[CH2:17][CH2:18]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3CCCO3)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(tetrahydrofuran-2-yl)methanone, the title compound was obtained as a white solid (47% yield). 1H NMR (400 MHz, CDCl3) δ 8.12-7.88, 6.97, 4.64-4.60, 3.93-3.42, 2.56-2.35, 2.10-1.93, 1.52-1.38, 0.84-0.62, 0.50-0.38, 0.17-0.05. MS (ES+) m/z 374.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]>>[F:14][C:15]1[CH:20]=[C:19]([C:11](=[O:13])[CH2:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:18]=[CH:17][C:16]=1[O:21][CH3:22]
Reactant: COc1ccc(CC(=O)O)cc1F
Reactant: COc1ccccc1F
Product: COc1ccc(CC(=O)c2ccc(OC)c(F)c2)cc1F
Yield: 77.5 %

Procedure:
Using 3-fluoro-4-methoxyphenylacetic acid and 2-fluoroanisole as starting materials, the procedures of Preparation Example 7 were repeated likewise, whereby the title compound was obtained in a yield of 77.5%.
Reaction SMILES: ClC1C=CC([N:8]2[CH:16](S)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=C(F)C=1.C1(N2C(=[O:31])C3=CC=CC=C3C2=S)C=CC=CC=1>C1(C)C=CC=CC=1>[C:9]1(=[O:18])[NH:8][C:16](=[O:31])[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=[C:10]12
Reactant: O=C1c2ccccc2C(=S)N1c1ccccc1
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2ccccc21

Procedure:
In 30 ml of toluene were dissolved 3.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol 1-one and 2.8 g of N-phenylthio-phthalimide, and the solution was heated under reflux for 3 hours. Upon cooling, there resulted crystals (phthalimide), which were filtered out, and the filtrate was concentrated under reduced pressure. A small amount of toluene was added and, upon standing overnight, there resulted crystals, which were collected by filtration and dried, thereby producing 2.7 g (yield of 67%) of the subject compound. Recrystallization from toluene yielded white crystals m.p. 127°-129° C.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Br:37])[CH:31]=1>>[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH:38][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Br:37])[CH:31]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(3-bromo-4-fluoro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=10.57 min. MS (ESI+): mass calcd. for C23H17BrFIN4O5S2, 719.34; m/z found, 719/721 [M+H]+. 1H NMR (500 MHz, CDCl3): 11.31 (s, 1H), 8.36 (dd, J=7.0, 0.7, 1H), 8.22 (dd, J=8.8, 0.7, 1H), 8.08 (d, J=1.5, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.32 (dd, J=8.2, 1.5, 1H), 7.23 (dd, J=6.5, 2.1, 1H), 7.06-6.99 (m, 1H), 6.98-6.89 (m, 2H), 6.46 (d, J=6.9, 1H), 4.93 (q, J=5.5, 1H), 3.82 (s, 3H), 3.25-3.08 (m, 2H).
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([CH:27]=O)[CH:18]=1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:27]([C:19]2[CH:18]=[N:17][C:26]3[C:21]([CH:20]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1cnc2ccccc2c1
Product: CC(C)N1C(=O)NC(c2cnc3ccccc3c2)c2cc3c(cc21)OCO3
Yield: 14 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (308 mg) and 3-quinolinecarboxaldehyde (243 mg) by the procedure described in example 10 in 14% yield. mp: 202-205° C. 1H NMR (CDCl3): 8.89 (d, J=2.0, 1H), 8.11 (d, J=7.6, 1H), 8.05 (s, 1H), 7.80 (d, J=7.6, 1H), 7.74 (t, J=7.6, 1H), 7.58 (t, J=7.6, 1H), 6.72 (s, 1H), 6.41 (s, 1H), 5.94 (s, 1H), 5.92 (s, 1H), 5.52 (d, J=1.9, 1H), 5.25 (s, 1H), 4.42 (m, 1H), 1.57 (d, J=7.0, 3H), 1.56 (d, J=7.0, 3H).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:11](=[O:43])[NH:12][C@@H:13]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:14]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C@H:17]1[C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH3:35])=[O:15])[CH3:10])C)(C)(C)C.Cl.C(Cl)[Cl:47]>O1CCOCC1>[ClH:47].[F:34][C:32]1[CH:31]=[CH:30][C:29]([CH3:35])=[C:28]([CH:33]=1)[CH2:27][NH:26][C:25]([C@@H:17]1[CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]1[C:14](=[O:15])[C@@H:13]([NH:12][C:11](=[O:43])[C@@H:9]([NH:7][CH3:6])[CH3:10])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:36]
Reactant: ClCCl
Reactant: Cc1ccc(F)cc1CNC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ccccc2C[C@H]1C(=O)NCc1cc(F)ccc1C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
((S)-1-{(S)-2-[(S)-2-(5-Fluoro-2-methyl-benzylcarbamoyl)-2,3-dihydro-indol-1-yl]-2-oxo-1-phenyl-ethylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (48 mg) was suspended in a 1:1 mixture of 4 M HCl in dioxane) and DCM and stirred at rt for 1 h. The solvent was removed in vacuo and the resulting solid was dissolved in CH3CN and water (3:1), and lyophilized to give (S)-1-[(S)-2-((S)-2-methylamino-propionylamino)-2-phenyl-acetyl]-2,3-dihydro-1H-indole-2-carboxylic acid 5-fluoro-2-methyl-benzylamide hydrochloride salt as a white powder (44 mg), m/z=503 (M+H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[BrH:21].N([O-])=O.[Na+]>O>[Br:21][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)c1ccc(C2CCCCC2)c(Br)c1

Procedure:
To 11.1 g. (0.044 moles) of ethyl 3-amino-4-cyclohexylphenylglyoxylate suspension in 225 ml. of 40$ hydrobromic acid and cooled to 0°C is added dropwise a solution of 2.34 g. of sodium nitrite in 30 ml. of water. To this mixture is added a solution of 20 g. of cuprous bromide in 350 ml. of 40% hydrobromic acid added portion wise and stirred for 15 hours. The reaction mixture is then poured onto ice water, extracted with chloroform, dried over sodium sulfate and concentrated in vacuo. The residue is then crystallized to obtain 3-bromo-4-cyclohexylphenylglyoxylic acid.
Reaction SMILES: [K].[CH3:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][NH:6][C:5](=[O:15])[N:4]=1.[CH3:16]I>CO>[CH3:16][N:6]1[C:5](=[O:15])[N:4]=[C:3]([CH3:2])[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7]1
Reactant: CI
Reactant: Cc1nc(=O)[nH]nc1-c1ccccc1
Agent: [K]
Solvent: CO
Product: Cc1nc(=O)n(C)nc1-c1ccccc1
Yield: 56.3 %

Procedure:
Potassium salt of 5-methyl-6-phenyl1,2,4-triazin-3(2H)-one (20 g) was dissolved in methanol (200 ml). Methyl iodide (37.8 g) was added thereto, and the solution was refluxed for 2.5 hours, and evaporated under reduced pressure. The resultant residue was washed with water and dissolved in chloroform. The solution was washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was washed with ethyl acetate and dried to give 2,5-dimethyl-6-phenyl-1,2,4-triazin-3(2H)-one (12.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:30]#[N:31])=[C:11]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]2[N:13]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](F)[CH:19]=3)=[CH:16][N:17]=2)[CH:14]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:30]#[N:31])=[C:11]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]2[N:13]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:19]=3)=[CH:16][N:17]=2)[CH:14]=1
Reactant: C1COCCN1
Reactant: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccnc(F)c3)cnc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccnc(N4CCOCC4)c3)cnc12
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-(2,4-dichloro-phenyl)-3-(2-fluoro-pyridin-4-yl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carbonitrile (46.6 mg, 0.10 mmol) and morpholine (0.045 mL, 0.51 mmol) in DMSO (0.8 mL) was heated at 180° C. and stirred for 30 min. The reaction mixture was cooled to RT, diluted in AcOEt (20 mL) and washed with water (2×10 ml). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to yield the crude 6-(2,4-dichloro-phenyl)-8-isobutoxy-3-(2-morpholin-4-yl-pyridin-4-yl)-imidazo[1,2-a]pyridine-7-carbonitrile intermediate.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([O:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH3:32]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:37][CH2:36][CH2:35][CH2:34][O:33][CH2:31][CH3:32])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CCOCCCN
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: CCOCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[21.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 24.2 mg (0.23 mmol) of 3-ethoxypropylamine are reacted together by general method E. 23.6 mg (36.9% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[C:4]([OH:11])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[C:8]([O:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 12 h

Procedure:
A mixture of 4-methylsalicyclic acid (20 g), benzylbromide (33 ml) and potassium carbonate (36.3 g ) in DMF (100 ml) was stirred for 12 hours. The mixture was poured into water (300 ml) and extracted three times with diethylether (100 ml each time). The combined organic extracts were washed with water and dried. Removal of the solvent gave benzyl 2-benzyloxy-4-methylbenzoate acid as a yellow liquid, yield 45 g.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[F:30][C:31]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[C:37]([CH3:38])[C:31]=3[F:30])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cccc(N)c1F
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3F)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 99.7 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.24 mmol) obtained in Example 19, step 4 and 2-fluoro-3-methylaniline (46 mg, 0.36 mmol), the title compound (120 mg, 99%) was obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:39])[C:23]([C:36]([OH:38])=[O:37])=[CH:24][N:25]4[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])=[CH:20][C:19]=3[F:40])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2)=O)(C)(C)C.[ClH:41]>>[ClH:41].[NH2:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:39])[C:23]([C:36]([OH:38])=[O:37])=[CH:24][N:25]4[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])=[CH:20][C:19]=3[F:40])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2
Reactant: CC(C)(C)OC(=O)NCC12CN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3F)CC1CCO2
Agent: Cl
Product: NCC12CN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3F)CC1CCO2

Procedure:
In an analogous manner to Example 1B, the product from step A is reacted with half-concentrated hydrochloric acid to give 7-(1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride with a melting point of 235° C. (with decomposition).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([SH:13])[N:6]=1.Cl[C:15]1[S:16][CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>O.C(O)C>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[N:6]=[C:7]([S:13][C:15]2[S:16][CH:17]=[CH:18][C:19]=2[N+:20]([O-:22])=[O:21])[N:8]=1
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: COc1cc(OC)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)nc(Sc2sccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
Sodium hydroxide (1.2 g) was dissolved in water (50 ml), 4,6-dimethoxy-2-mercaptopyrimidine (5.3 g) was added, and the mixture was stirred at room temperature for 15 minutes. 2-Chloro-3-nitrothiophene (5.0 g) dissolved in ethanol (50 ml) was added with stirring, the mixture being stirred at room temperature for 6 hours. The resulting precipitate was filtered, washed with water and dried, to give 7.6 g of the desired product, mp 199°-201° C.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10](=O)[C:11]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13][C:12]=2[N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:41]>C(#N)C>[CH2:1]([C:8]1[N:9]=[C:10]([Cl:41])[C:11]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13][C:12]=2[N:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2nc(Cc3ccccc3)[nH]c(=O)c2CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCc2nc(Cc3ccccc3)nc(Cl)c2CC1
Temperature: 80 °C
Yield: 85.8 %

Procedure:
To a suspension of the product from step A (4 g, 10 mmol) in acetonitrile (100 ml) was added N,N-dimethylaniline (1.4 ml, 11.3 mmol), followed by careful addition of POCl3 (9.6 ml, 100 mmol). The resulting brown solution was heated at 80° C. for 4 h. The reaction mixture was concentrated in vacuo, azeotroped with PhMe (×2) and DCM. The residue was partitioned between 2 N HCl and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield 3.5 g (84%) of title compound as brown oil, which solidified on standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:31]=[C:32]3[C:36](=[C:37]([CH3:39])[CH:38]=2)[N:35]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:34]=[CH:33]3)=[O:29])[CH:23]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:31]=[C:32]6[C:36](=[C:37]([CH3:39])[CH:38]=5)[N:35]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[N:34]=[CH:33]6)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2cnn(COCC[Si](C)(C)C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(cnn5COCC[Si](C)(C)C)c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
36 mg (0.13 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 50 mg (0.12 mmol) (6-chloro-pyrimidin-4-yl)-[7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-indazol-5-yl]-methanone and 30 μL (0.21 mmol) TEA were combined in 0.5 mL DMF and stirred overnight at RT. The reaction mixture was mixed with ice water, the product precipitated as a solid was filtered off and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]([O:18]CC)=[O:17])=[N:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]([OH:18])=[O:17])=[N:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)c1nc2cccnc2n(-c2ccc(C)c(F)c2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-n2c(=O)c(C(=O)O)nc3cccnc32)cc1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
45 g (0.14 mol) of ethyl 4-(3-fluoro-4-methylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylate was dissolved in 1,4-dioxan (300 ml), and a solution of 39 g (0.28 mol) of potassium carbonate and water (300 ml) was added thereto. The solution was stirred for 1 hour at 60° C. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. Water was added to the residue thus obtained and was washed with chloroform. Then, the aqueous layer was adjusted to pH 1 by adding 6 N hydrochloric acid, and the aqueous layer was extracted again with chloroform. Anhydrous magnesium sulfate was added to the organic layer to dry the layer, and the solvent was distilled off under reduced pressure to obtain 32 g (yield: 76%) of 4-(3-fluoro-4-methylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylic acid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[NH:5][C:4]1=[O:15])[CH3:2].C(=O)([O-])[O-].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27]>CN(C)C=O>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[C:4]1=[O:15])[CH3:2]
Reactant: CC(C)(O)CCCCCBr
Reactant: CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCn1cnc2c1c(=O)n(CCCCCC(C)(C)O)c(=O)n2CC

Procedure:
6.2 g of 3,7-diethylxanthine, 4.1 g of ptassium carbonate, and 6.6 g of 1-bromo-6-hydroxy-6-methylheptane are stirred in 100 ml of dimethylformamide at 120° C. for 18 hours. The mixture is filtered hot with suction, the filtrate is concentrated under recuced pressure final recrystallization from diisopropylether with addition of petroleum ether.