Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: c1cocn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Yield: 23 %

Procedure:
The title compound (20 mg, 23%) was prepared from oxazole (60 mg, 0.81 mmol) and (R)-2-[4-(4-iodo-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.2 mmol) using the procedure of Example 146, step 1; 1HNMR (400 MHz, CDCl3) δ 7.95 (d, J=8.4 Hz, 2H), 7.68 (d, J=0.8 Hz, 1H), 7.26 (m, 2H), 7.21 (d, J=0.8 Hz, 1H), 7.10 (d, J=8 Hz, 2H), 6.86 (br d, J=7.2 Hz, 2H), 4.10 (br, 2H), 3.96 (s, 2H), 3.9-3.75 (br, 2H), 3.40 (br, 2H), 2.03-1.84 (br, 4H), 1.46 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[Br:14][C:15]1[C:16](F)=[C:17]2[C:23]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1.CC#N.O>CCCCO>[Br:14][C:15]1[C:16]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[C:17]2[C:23]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Solvent: CCCCO
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 160 °C
Reaction time: 24 h
Yield: 35.1 %

Procedure:
(R)-tert-Butyl pyrrolidin-3-ylcarbamate (333 mg, 1.79 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (200 mg, 0.597 mmol) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours. The reaction was concentrated to dryness, and then the residue was purified by chromatography (SP4, C-18 25M+ column, gradient of 10-90% CH3CN/water, 30CV) to yield (R)-tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (105 mg, 35.1% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1.[C:15]([Cl:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[ClH:23].[CH3:12][N:8]1[CH2:7][C:6]([CH3:14])([CH3:13])[C:5]2[N:4]=[CH:3][C:2]([NH:1][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:10]=2[CH2:9]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1Cc2cc(N)cnc2C(C)(C)C1
Solvent: C1CCOC1
Product: CN1Cc2cc(NC(=O)c3ccccc3)cnc2C(C)(C)C1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6]naphthyridine (96 mg, 0.50 mmol) was dissolved in dry THF (5 ml) and the solution treated with benzoyl chloride (70.3 mg; 0.50 mmol). The mixture was stirred at ambient temperature for 2 h then the precipitate collected by filtration, washed with THF, diethyl ether and dried in vacuo (132 mg; 80%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]#[N:6].[CH3:7][OH:8].[ClH:9]>C1(C)C=CC=CC=1>[ClH:9].[CH3:7][O:8][C:5](=[NH:6])[CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCC#N
Reactant: CO
Agent: Cl
Solvent: Cc1ccccc1
Product: COCCC(=N)OC
Temperature: 3 °C
Reaction time: 2.25 h
Yield: 80 %

Procedure:
To a three-necked reaction vessel equipped with stirrer, gas delivery tube, thermometer and reflux condenser is charged 85.1 parts of 3-methoxypropionitrile, 32.0 parts of reagent grade methanol and 300 parts of toluene. The exit from the reflux condenser is connected to a drying tower filled with a commercially available drying agent and a bath is provided for cooling the vessel below 0° C. Hydrochloric acid gas flow is controlled by means of a rotameter and is passed through a calcium chloride filled trap which serves both as a means for drying the gas and as a receiver in case liquid is sucked back into the line. After charging the reagents and toluene, the solution is stirred and cooled to 3° C. and the HCl gas is then fed, while controlling the temperature to -4° to 1° C., until 38.0 parts have been added. The HCl gas is added as rapidly as possible commensurate with complete adsorption and good temperature control. The mixture is then stirred for 15 hours in an ice bath (maximum 10° C.). Crystals of methyl-3-methoxypropionimidate hydrochloride appear 2.25 hours after the HCl addition is complete. 46.5 Hours after the HCl addition is stopped, an 80% yield of methyl-3-methoxypropionimidate hydrochloride is formed.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.O>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[CH3:11])=[N:14][CH:15]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ccc(C(F)(F)F)cn1
Yield: 74016.1 %

Procedure:
3.04 g (0.02 mmol) of 2-amino-4-nitrotoluene and 7.26 g (0.04 mol) of 2-chloro-5-trifluoromethylpyridine are stirred in the molten state for 5 hours at 160° C. After cooling, 200 ml of water are added thereto and the product is taken up in methylene chloride. The solvent is evaporated off and the residue is purified by column chromatography (silica gel, methylene chloride:hexane=2:1), affording 4.4 g of N-(5-trifluoromethyl-2-pyridyl)-2-methyl-5-nitroaniline (m.p. 103°-105° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH:2]=1.[H][H].Cl>CO.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:2]1
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4cccnc4)cc3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCNC4)cc3)oc12
Yield: 48.7 %

Procedure:
2-(4-(Pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (550 mg, 1.66 mmol) and platinum (IV) oxide (110 mg) in methanol (100 ml) was hydrogenated under 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (dichlormethane:methanol=9:1) to give the solid. The solid was acidified by hydrochloride acid and wash with ethyl acetate. The solvent was removed in vacuum. 260 mg of 2-(4-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained. Yield: 47%. LC-MS (ESI) m/z: 322 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:27]([CH3:29])[CH3:28])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:4][CH:3]=1.[NH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.[CH3:44][OH:45].ClCCl>>[O:8]=[C:7]1[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:27]([CH3:29])[CH3:28])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:21])[CH3:22])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:4][CH:3]=[C:2]1[NH:1][C:44]([NH:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)=[O:45]
Reactant: CO
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reactant: NCc1cccnc1
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2cccnc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F

Procedure:
2-(5-Amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide and 3-aminomethylpyridine were subjected to a method similar to that described in Example 3.a. Chromatography, with methanol: dichloromethane (5:95) as the eluent, gave 2-[6-oxo-2-phenyl-5-[3-(3-pyridyl)methylureido]-1,6-dihydro-1-pyrimidinyl]-N-(2-tert-butyldimethysilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide as a white solid; MS: m/z=647(M+1).
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[NH:7][CH:8]=1.Br[CH2:12][CH2:13][OH:14].C(O)(=O)C>O1CCOCC1>[OH:14][CH2:13][CH2:12][N:7]1[CH:8]=[C:4]([I:3])[CH:5]=[C:6]1[CH:9]=[O:10]
Reactant: O=Cc1cc(I)c[nH]1
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=Cc1cc(I)cn1CCO
Temperature: 60 °C
Yield: 50 %

Procedure:
Potassium hydroxide (3.1 g, 54.3 mmol) was added to a stirred solution of 4-iodo-1H-pyrrole-2-carbaldehyde (4.0 g, 18.1 mmol) in dioxane (20 mL). 2-Bromo-ethanol (2.56 mL, 36.2 mmol) was added to the reaction mixture and heated at 60° C. for 16 h. The reaction mixture was cooled to room temperature and the pH was adjusted to ˜6 by the addition of acetic acid. The reaction mixture was then concentrated in vacuo to give a residue which was partitioned between water and ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate in petroleum ether as eluent to afford 1-(2-hydroxyethyl)-4-iodo-pyrrole-2-carbaldehyde (2.4 g, 50%) as a colourless solid.
Reaction SMILES: Cl[C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1[NH2:8].CCN(CC)CC.[H][H]>CO.[Pd]>[F:10][C:5]1[C:6]([F:9])=[C:7]([NH2:8])[CH:2]=[C:3]([F:11])[N:4]=1
Reactant: [H][H]
Reactant: Nc1c(F)c(F)nc(F)c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1cc(F)nc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A mixture of 3-chloro-2,5,6-trifluoro-pyridin-4-ylamine (1.82 g, 10 mmol), 5% Pd/C (0.5 g), and Et3N (3.04 g, 30 mmol) in 50 mL of MeOH was equipped with a balloon of hydrogen gas and stirred at room temperature overnight. The solution was filtered through diatomaceous earth (Celite®). The filtrate was concentrated under vacuum and the residue was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 1.33 g (90%) of the desired product. MS (DCI) m/e 149 (M+H)+.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)[O:2][C:3](C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO[C:22]1[CH:29]=[C:28]([OH:30])[C:27]([Cl:31])=[CH:26][C:23]=1[CH:24]=O.Cl>C(Cl)Cl>[CH3:3][O:2][C:29]1[CH:22]=[C:23]([CH2:24][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:26]=[C:27]([Cl:31])[C:28]=1[OH:30]
Reactant: C1CCNC1
Reactant: COc1cc(O)c(Cl)cc1C=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(CN2CCCC2)cc(Cl)c1O
Yield: 24.3 %

Procedure:
NaB(OAc)3H (12.5 g, 0.098 mol) was added in portions for 15 min to a mixture of pyrrolidine (5.41 mL, 0.087 mol) and 2-methoxy-5-chloro-4-hydroxybenzaldehyde (12.5 g, 0.089 mol) in CH2Cl2 (100 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (18 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 9 (30 mL) and extracted with chloroform (2×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give compound (5.1 g, 75%) was obtained as white crystals. LCMS-data: 242.0 (M+H)+, (calculated for C12H16NOCl 241.5). 1H NMR (400 MHz)-data (DMSO-d6, J, Hz): 9.18 (br s, 1H, OH); 6.83 (s, 2H, ArH); 3.79 (s, 3H, CH3); 3.44 (s, 2H, CH2Ar); 2.36-2.44 (m, 4H, CH2CH2CH2CH2,); 1.65-1.72 (m, 4H, CH2CH2CH2CH2,).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][O:17][CH3:18])=[CH:12][CH:13]=2)[O:8][CH2:7][C:6]1([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][CH3:29])=[CH:22][CH:21]=1)[CH3:19].[F:30][C:31]([F:47])([C:43]([F:46])([F:45])[F:44])[CH2:32][CH2:33][CH2:34][S:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=O)=[O:36].C([BH3-])#N.[Na+].C(Cl)(Cl)Cl.CO.O.N>CO.O>[CH3:18][O:17][CH2:16][O:15][C:11]1[CH:10]=[C:9]2[C:14]([CH:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][S:35]([CH2:34][CH2:33][CH2:32][C:31]([F:47])([F:30])[C:43]([F:44])([F:45])[F:46])=[O:36])[C:6]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][O:28][CH3:29])=[CH:24][CH:25]=3)([CH3:19])[CH2:7][O:8]2)=[CH:13][CH:12]=1
Reactant: O=CCCCCS(=O)CCCC(F)(F)C(F)(F)F
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCN)cc1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCNCCCCCS(=O)CCCC(F)(F)C(F)(F)F)cc1
Reaction time: 2 h
Yield: 29.4 %

Procedure:
To a solution of (3RS,4RS)-4-(3-aminopropyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (80 mg, 0.20 mmol) and 5-(4,4,5,5,5-pentafluoropentylsulfinyl)pentanal (80 mg, 0.19 mmol) in methanol (5 ml) was added a solution of sodium cyanoborohydride (12 mg, 0.19 mmol) in methanol (5 ml), which was then stirred at 0 for 2 hours. The reaction solution was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to preparative TLC on silica gel using chloroform/methanol/ammonia water (7/1/0.1) as a mobile phase to give (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-{3-[N-5-(4,4,5,5,5-pentafluoropentylsulfinyl)pe ntylamino]propyl}chroman (38 mg, yield 28%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)=[O:6].[C:23](Cl)(=[O:31])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:3]([NH:2][C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:31])=[C:4]([CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)=[O:6]
Reactant: Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2)Oc1ccccc1
Yield: 88 %

Procedure:
2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide hydrochloride (100 mg) was reacted with 50 μl of phenyl chlorocarbonate in 5 ml of tetrahydrofuran in the presence of 150 μl of diisopropylethylamine. The reaction mixture was subjected to extraction with ethyl acetate and water and recrystallization from ethyl acetate/hexane to give 110 mg of 5-chloro-N-(3,4-methylenedioxybenzyl)-2-phenoxycarbonylaminobenzamide (yield: 88%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:3])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: Nc1ccc(Cn2ccnc2)cn1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(Cn4ccnc4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 5-imidazol-1-ylmethyl-pyridin-2-ylamine (Step 120.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 3 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 503.1 [M+H]+; tR=3.76 min (System 1); TLC: Rf=0.47 (DCM/MeOH, 9:1).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.CS(C)=[O:23].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(O)(C)C>O>[CH3:10][C@@H:7]1[N:6]2[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13]([C:14]3=[CH:15][C:2]([F:1])=[C:3]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)[C:4](=[C:5]23)[O:9][CH2:8]1)=[O:16].[CH3:10][C@@H:7]1[N:6]2[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13]([C:14]3=[CH:15][C:2]([F:1])=[C:3]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)[C:4](=[C:5]23)[O:9][CH2:8]1)=[O:16].[OH2:23]
Reactant: CS(C)=O
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCNCC1
Solvent: O
Solvent: CC(C)O
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 80 °C

Procedure:
In 1 liter reactor equipped with a mechanical stirrer, a condenser and a thermometer, heated at 80° C., was charged 87.5 g (0.31 mole) of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, 61.3 mL DMSO and 86.3 mL (0.77 mole) of N-methylpiperazine. The slurry was stirred at a rate of 250 rpm under nitrogen atmosphere at 80° C. until completion of the reaction (monitoring by HPLC). Then the slurry was cooled to 75° C. and a mixture of isopropanol (675 mL) and water (25 mL) was added dropwise at this temperature during 2 hours. The slurry was then cooled to 5° C. during 4 hours, maintained at this temperature for 2 hours and filtrated under vacuum at this temperature. The solid was then washed with 175 mL of isopropanol (2 rinses) and dried under vacuum to obtain levofloxacin hemihydrate.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C[Si]([C:23]#[C:24][C:25]1[N:30]2[N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=[C:29]2[CH:28]=[CH:27][CH:26]=1)(C)C>C1COCC1.C(#N)C>[C:24]([C:25]1[N:30]2[N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:38][CH2:39]3)=[O:36])[N:33]=[C:29]2[CH:28]=[CH:27][CH:26]=1)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1cccc2nc(NC(=O)C3CC3)nn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Product: C#Cc1cccc2nc(NC(=O)C3CC3)nn12
Temperature: 25 °C
Yield: 96.7 %

Procedure:
TBAF (0.4 mmol) 1M solution in THF is added to a solution of cyclopropanecarboxylic acid (5-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (0.32 mmol) in acetonitrile (4 mL) at room temperature. The reaction mixture is stirred at room temperature until all the starting material disappears by LCMS. The solvent of the reaction is removed under vacuum, and the mixture is redissolved in ethyl acetate. The organic phase is washed with water. The organic layer is dried over MgSO4, filtered and the solvent is removed under vacuum to afford the pure product (70 mg, 97% yield). No further purification is carried out on the product.
Reaction SMILES: [NH:1]([C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)=[O:4])[NH2:2].CCO[C:40](OCC)(OCC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(O)C>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:25][CH:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:3]3[O:4][C:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[N:2][N:1]=3)=[CH:7][CH:8]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)NN)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cc3nnc(-c4ccccc4)o3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
A mixture of 60 mg (0.12 mmol) of tert-butyl (3RS,4RS)-4-(4-hydrazinocarbonylmethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate and 27.7 μl (0.12 mmol) of triethyl orthobenzoate in 5 ml of ethanol was boiled under reflux for 18 hours. After cooling the mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 30 mg (44% of theory) or tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenyl]-piperidine-1-carboxylate as a colourless foam; MS: 575 (M+H)+.
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[Cs+].[Cs+].[Cl:9][C:10]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[Cl:9][C:10]1[CH:19]=[C:18]([N:20]([CH3:3])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(N(C)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
78 μL of iodomethane and 447 mg of Cesium Carbonate were added to 300 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in 3 mL of DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 2-chloro-4-(N-methylmethylsulfonamido)benzoate. 295 mg of methyl 2-chloro-4-(N-methylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 249 mg of 2-chloro-4-(N-methylmethylsulfonamido)benzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:38][CH3:39])[CH2:28][CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:26].CO>CN1CCCC1=O>[CH2:38]([N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35][C:12]2[N:13]=[CH:14][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=4)[C:20](=[O:21])[N:19]([CH3:22])[C:10]=3[N:11]=2)=[CH:36][CH:37]=1)[CH3:39]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(S(C)(=O)=O)nc21
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCN(CC)CCOc1ccc(Nc2ncc3cc(Oc4ccc(F)cc4)c(=O)n(C)c3n2)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8-Step A-B, 0.35 g, 1 mmol) and 4-(2-diethylaminoethoxy)aniline (0.625 g, 3 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the free amine. This was suspended in ethyl acetate (1-2 mL), hydrochloric acid in ether (1M, 1.2 eq) was added and the reaction was stirred for 30 minutes. Isolation of the solid via filtration and drying provided 0.085 g of the hydrochloride salt (Mass spec. M+1=478, MP=245.2-246.1° C.).