Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.[CH2:19]([N:25]([CH3:29])[C:26](Cl)=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:26](=[O:27])[N:25]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:29])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: CCCCCCN(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCN(C)C(=O)OC1CCN(C)C(=O)N1c1nnc(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-hexyl-N-methylcarbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(N-hexyl-N-methylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C-]#N.[Na+].[N:30]12CCN(CC1)C[CH2:31]2.O>CS(C)=O>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:12][CH:11]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:31]#[N:30])[N:7]=1
Reactant: C1CN2CCN1CC2
Reactant: CC(C)(C)CN(Cc1ccc(Cn2cncn2)cc1)c1ccnc(Cl)n1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)CN(Cc1ccc(Cn2cncn2)cc1)c1ccnc(C#N)n1
Temperature: 70 °C
Reaction time: 5 h
Yield: 69167.1 %

Procedure:
(2-Chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-[1,2,4]triazol-1-ylmethyl-benzyl)-amine (160 mg, 0.43 mmoles) and sodium cyanide (0.1 g, 2.2 mmoles) are dissolved in 5 ml of DMSO and 1,4-diaza bicyclo[2,2,2]octane (23 mg, 0.2 mmoles) is added at rt. The mixture is stirred at rt for 5 h at 70° C. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesum sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 50 g of desired 4-[(2,2-dimethyl-propyl)-(4-[1,2,4]triazol-1-ylmethyl-benzyl)-amino]-pyrimidine-2-carbonitrile in 32% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[C:17](OC)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH3:20])[C:17](=[O:21])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: COc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: C=C(C)C(=O)OC
Solvent: C1CCOC1
Product: COc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
3-bromo-6-methoxycarbazole (20 g) produced in Example 1, step 1 was dissolved in anhydrous tetrahydrofuran (200 ml), and to the solution were added methyl methacrylate (77.6 ml), then Triton B (0.7 ml). The mixture was heated under reflux in an argon atmosphere for 2 hours, and the solvent was evaporated under reduced pressure. The resulting residue was suspended in methanol (60 ml), and sodium hydroxide (6.4 g) dissolved in water (80 ml) was added dropwise at room temperature, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and water and ether were added for phase separation. The aqueous layer was rendered acidic by addition of 4N hydrochloric acid, and ethyl acetate was added for further phase separation. The ethyl acetate layer was washed with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residual crude crystals were washed with hexane and ether and recovered by filtration to obtain the title compound (25.0 g, 95%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[C:29]2[C:25]([C:26](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]cc(CCC(=O)O)c1C
Yield: 86.6 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (217 mg), 239 mg 6-(2-methoxyphenyl)-2-oxindole and 3 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 348 mg (86%) of the title compound as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:17][OH:18]>C(O)C.[OH-].[Na+].C1CCCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:17][OH:18])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=C(Cc1ccccc1)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CCO
Product: ON=C(Cc1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
This compound was prepared by suitable modification of the procedures described by Niemers and Hiltman, Synthesis, 1976, 593 as follows. To a solution of 1-(2-pyridinyl)-2-phenylethanone (Case and Buttle, J. Org. Chem., 1961, 26, 4415) (49.05 g, 0.249 mol) in 95% ethanol (400 ml) was added a solution of hydroxylamine hydrochloride (51.91 g, 0.747 mol) in 10% sodium hydroxide (200 ml). The solution was heated to reflux under nitrogen for 1.25 hours, and stirred at room temperature for 48 hours. The majority of the solvent was removed and the residue was added to water (500 ml). The aqueous solution was extracted with ether (1×1000 ml, and 3×250 ml). The combined ether extracts were washed with saturated NaCl and dried over MgSO4. Removal of solvent gave 55.61 g of the crude product as a brown solid. The above solid was dissolved in cyclohexane (400 ml) and ether (500 ml) and filtered while hot. The filtrate was concentrated to a volume of 500 ml and cooled to room temperature. The solid which formed was isolated by filtration to yield 20.77 g of 1-(2-pyridinyl)-2-phenylethanone oxime; mp 151°-153° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]12[NH:13][CH:12]1[CH2:11][N:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=1[F:31])[CH2:9]2.C(N(CC)CC)C>ClCCl>[C:1]([N:13]1[CH:12]2[CH:8]1[CH2:9][N:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=1[F:31])[CH2:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC4NC4C3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC4C(C3)N4C(C)=O)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Acetic anhydride (3.5 μL, 0.05 mmol) was added to a cooled (0° C.) solution of N-({(5S)-3-[4-(3,6-diazabicyclo[3.1.0]hex-3-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (12 mg, 0.036 mmol) in triethylamine (10 μL, 0.072 mmol) and dichloromethane (0.7 mL). After 1 hour, the solution was diluted with dichloromethane, and washed with dilute NaHCO3, brine, and dried (MgSO4), filtered and concentrated. Purification by pTLC (4% MeOH—CH2Cl2) provided the title compound.
Reaction SMILES: [CH2:1]1[O:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=2)[O:3][CH2:2]1.P(OCC)(OCC)OCC.C[O-].[Na+].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[CH:28]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:1]1[O:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8](/[CH:11]=[CH:33]/[C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[CH:7][CH:6]=2)[O:3][CH2:2]1
Reactant: ClCc1ccc(C2OCCO2)cc1
Reactant: O=Cc1cccnc1
Agent: CCOP(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C(=C/c1cccnc1)\c1ccc(C2OCCO2)cc1
Temperature: 5 °C
Yield: 84.9 %

Procedure:
10.11 g (50.9 mmol) of 4-chloromethylbenzaldehyde ethylene acetal and 8.46 g (50.9 mmol) of triethyl phosphite were heated without solvent, with magnetic stirring, at an oil bath temperature of 200°-210° C. until gas evolution was complete (about 1 h). After cooling, 70 ml of dimethylformamide (filtered through basic alumina, activity I) and 5.5 g (102.0 mmol) of sodium methylate were added. The mixture was cooled to 5° C. and, with magnetic stirring and cooling, a solution of 5.45 g (50.9 mmol) of pyridine-3-aldehyde in 20 ml of dimethylformamide was added dropwise within 15 min (during which the temperature rose to 25° C.), and the mixture was then stirred at room temperature for 1 h. The reaction mixture was diluted with 250 ml of toluene and washed twice with water. The combined wash phases were extracted twice with toluene. Drying of the combined organic phases over magnesium sulfate and removal of the solvent in vacuo provided 10.94 g of a yellowish solid. Recrystallization from cyclohexane produced 8.74 g, and working up of the mother liquor produced a further 0.60 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:7]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C.CCOC(C)=O>[N:31]([CH2:24][CH2:23][O:22][C@@H:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:30])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:32]=[N-:33]
Reactant: Cc1ccc(Cl)cc1[C@H](OCCOS(C)(=O)=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1[C@H](OCCN=[N+]=[N-])[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 93.5 %

Procedure:
(R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (8.4 g, 18.3 mmol) was dissolved in anhydrous DMF (150 mL), solid NaN3 (3.56 g, 54.8 mmoL) was added and the reaction mixture was heated to 60° C. for overnight. The reaction mixture was cooled to rt and diluted with EtOAc (500 mL), the organic phase was washed with water (5×50 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-((R)-(2-azidoethoxy)(5-chloro-2-methylphenyl)methyl)piperidine-1-carboxylate (7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:22][O:23][CH2:24][CH:25]([NH2:27])[CH3:26].C(OCC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:27][CH:25]([CH3:26])[CH2:24][O:23][CH3:22])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(Br)c1C(=O)OC
Reactant: COCC(C)N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COCC(C)Nc1cccc(C(=O)OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.9 %

Procedure:
To a stirred solution of 3-Bromophthalic acid dimethyl ester (0.82 g, 3.0 mmol) in toluene (20 mL), were added S-BINAP (56 mg, 0.09 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Cs2CO3 (1.37 g, 4.2 mmol), and 1-methoxy-2-propanamine (0.32 g, 3.6 mmol), and the resulting mixture was heated to reflux with stirring under nitrogen for 24 hours. The mixture was allowed to cool to room temperature, and diethyl ether was added (70 mL). The mixture was filtered, and the filtrate was evaporated in vacuo. The residue was chromatographed eluting with 17:3 hexanes-ethyl acetate. The resulting material was further purified by preparative HPLC, eluting with 11:9 water-acetonitrile, and providing 0.32 g of the product in 38% yield: 1H NMR (DMSO-d6) δ1.14 (d, J=6.4 Hz, 3H), 3.29 (s, 3H), 3.37 (d, J=4.8 Hz, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 3.74-3.80 (m, 1H), 6.53 (d, J=7.8 Hz, 1H), 6.76 (d, J=7.3 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1>[Pd].CCO.CO>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc([N+](=O)[O-])c2n1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1ccc2cccc(N)c2n1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Palladium on carbon (10%, 50 mg) was added to a solution of 2-methyl-8-nitroquinoline (500 mg, 2.66 mmol) in EtOH (40 ml) and the mixture was stirred under an atmosphere of hydrogen for 2 h. The mixture was diluted with MeOH (40 ml), filtered through celite and the filtrate was concentrated in vacuo to give the title compound (417 mg, 99%).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:16]I.[H-].[Na+]>C1COCC1.C(OCC)C>[C:12]([O:11][C:9]([N:1]([CH3:16])[C@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: CI
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.6 %

Procedure:
To a solution of N-Boc-D-Val-OH (1.0 g, 4.60 mmol) in THF (15.3 mL) at 0° C. was added MeI (2.88 mL, 46.0 mmol, 10.0 equiv). NaH (60%, 1.84 g, 46.0 mmol, 10.0 equiv) was added as a solid to the suspension over a period of 2 hours. After stirring for 12 hours at room temperature, the reaction mixture was diluted with diethyl ether and quenched with water slowly. Aqueous layer was extracted with diethyl ether followed by acidified to pH 3 with 10% citric acid and extraction with ethyl acetate. Combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.3a (1.07 g) which was used for the next step without further purification. MS m/z (M+Na) 254.2. 1H NMR (400 MHz, CDCl3) 4.02-4.17 (m, 1H), 2.88 (s, 3H), 2.40-2.14 (m, 1H), 1.54-1.39 (m, 9H), 1.03 (d, J=6.60 Hz, 3H), 0.92 (d, J=6.70 Hz, 3H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]S[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:25]([O-:29])([O-])(=[O:27])=S.[Na+].[Na+].C(OC([O-])=O)(OC(OC(C)(C)C)=O)=O>ClCCl>[O:27]=[S:25]1(=[O:29])[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCSCC1
Reactant: O=S([O-])([O-])=S
Agent: CC(C)(C)OC(=O)OC(=O)OC(=O)[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC1
Yield: 91.6 %

Procedure:
tert-Butyl thiomorpholine-4-carboxylate (1.91 g, 9.42 mol) was dissolved in dichloromethane (50 ml); m-chloroperbenzoic acid (5.0 g, 19 mmol) was gradually added while cooled with ice bath, stirred, and under nitrogen atmosphere; and the reaction mixture was stirred at room temperature for 12 hours. After addition of a saturated aqueous solution of sodium thiosulfate, the reaction mixture was kept stirred for a while; and this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Triethylamine (8.1 ml, 58 ml) were added to the obtained crystals; and the reaction mixture was stirred at room temperature. tert-Butoxycarbonyl dicarbonate (13.3 ml, 58 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure; and the obtained crystals were suspended with a solvent mixture of diethyl ether:ethanol=10:1, filtered off, washed with diethyl ether and dried under aeration to yield the title compound as colorless crystals (2.03 g, 8.63 mmol, 91.6%).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][N:33]([CH2:2][C:3]([N:5]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[O:9][CH2:8][CH2:7][CH2:6]4)=[O:4])[CH2:34][CH2:35]3)=[CH:26][CH:25]=2)=[CH:21][CH:22]=1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Reactant: O=C(CBr)N1CCCOc2ccccc21
Product: O=C(CN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (15) synthesized in Reference Example and the compound (5) synthesized in Reference Example were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [C:1]1([C:7]([NH:20][C@@H:21]([CH2:24][NH2:25])[CH2:22][OH:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:33]([C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[O:33]([C:40]1[CH:45]=[CH:44][C:43]([S:46]([NH:25][CH2:24][C@H:21]([NH:20][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][OH:23])(=[O:48])=[O:47])=[CH:42][CH:41]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: NC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-triphenylmethylamino-3-aminopropanol (1.99 g, 6 mmol) in CH2Cl2 (12 mL) at 0° C., triethylamine (1.7 mL, 12 mmol) was added dropwise followed by the addition of 4-phenoxybenzenesulfonyl chloride (1.61 g in 12 mL CH2Cl2). The reaction mixture was stirred at RT for 2 h and then was washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated and purified through column chromatography (silica gel, 35% EtoAc in pet. ether) to afford (S)-3-(4-phenoxybenzenesulfonamido)-2-(tritylamino)propanol as colorless solid in 74% (2.52 g) yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[BH4-].[Na+]>CN(C)C=O.CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N=Cc2cccc(F)c2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(NCc2cccc(F)c2)cn1
Reaction time: 1 h

Procedure:
The solution of 18.6 g of 5-(m-fluorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester in 50 ml of hot dimethylformamide is added all at once to the solution of 5.0 g of sodium borohydride in 230 ml of methanol at -20° while stirring. The mixture warms to approximately 0° and after one hour the mixture is warmed to 35° for 10-15 minutes. It is cooled, one-half of the methanol is distilled off and the cold concentrate is conbined with 2 ml of acetic acid and the solution of 9 ml of 12 N hydrochloric acid in 70 ml of ice water. The clear solution, (pH=6) is cooled and stirred while additional ice and water is added to cause the solution to become faintly cloudy. The precipitate is collected and recrystallized from aqueous methanol, to yield the 5-(m-fluorobenzylamino)-pyridine-2-carboxylic acid methyl ester melting at 89°-92°.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([CH3:13])[C:8](=[O:14])[C:7]=1[O:15][CH3:16])=[O:5])C.[OH-].[Na+]>CO>[CH3:16][O:15][C:7]1[C:8](=[O:14])[N:9]([CH3:13])[C:10]([CH3:12])=[CH:11][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(C)n(C)c(=O)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(=O)O)cc(C)n(C)c1=O
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of 16 (7.51 g, 33.3 mmol) in methanol (350 mL) was added a 4 M sodium hydroxide solution (350 mL). The resulting solution was heated at reflux, and after 2 h, methanol was removed under reduced pressure. An aqueous 3 N HCl solution was used to adjust the resulting solution to pH 1. The solution was extracted with ethyl acetate; the organic extracts were dried over sodium sulfate, and solvent was removed under reduced pressure to yield 6.44 g (98%) of 5 as a tan solid. 1H NMR (300 MHz, CD3OD): δ=2.40 (s, 3H, C—CH3), 3.58 (s, 3H, N—CH3), 3.86 (s, 3H, O—CH3), 6.36 (s, 1H, CH); 13C NMR (75 MHz, CD3OD): δ=20.6 (C—CH3), 32.6 (N—CH3), 61.0 (O—CH3), 105.9 (CH), 132.8, 143.4, 146.6, 162.6, 168.2; ESI-MS calcd for C9H11NO4 [M−H]−: 196.0610. found 196.0615.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:50]1[C:59]([N+:60]([O-:62])=[O:61])=[CH:58][CH:57]=[CH:56][C:51]=1[C:52]([NH:54][CH3:55])=[O:53].[F:63][C:64]1[CH:65]=[C:66]([NH2:70])[CH:67]=[N:68][CH:69]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:63][C:64]1[CH:65]=[C:66]([NH:70][C:50]2[C:59]([N+:60]([O-:62])=[O:61])=[CH:58][CH:57]=[CH:56][C:51]=2[C:52]([NH:54][CH3:55])=[O:53])[CH:67]=[N:68][CH:69]=1
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: Nc1cncc(F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CNC(=O)c1cccc([N+](=O)[O-])c1Nc1cncc(F)c1
Temperature: 100 °C

Procedure:
A mixture of cesium carbonate (1.55 g, 4.75 mmol), xantphos (550 mg, 0.950 mmol), 2-bromo-N-methyl-3-nitrobenzamide (820 mg, 3.17 mmol) (Prepared in Example 20), tris(dibenzylideneacetone)dipalladium (0) (580 mg, 0.63 mmol), 5-fluoropyridin-3-amine (532 mg, 4.75 mmol) in toluene (15 mL) under N2 was heated at 100° C. for 18 h. The mixture was cooled to rt and diluted with EtOAc. The mixture was filtered and the filtrates were concentrated in vacuo. Purification of the residue by flash chromatography over silica gel, using EtOAc as eluent gave 2-(5-fluoropyridin-3-ylamino)-N-methyl-3-nitrobenzamide: 1H NMR (400 MHz, CDCl3) δ 9.29 (1H, s), 8.23 (1H, s), 8.21 (1H, d, J=8.0 Hz), 8.16 (1H, s), 7.89 (1H, d, J=8.0 Hz), 7.26 (1H, t, J=8.0 Hz), 7.04 (1H, d, J=8.0 Hz), 6.41 (1H, br), 2.78 (3H, d, J=4.0 Hz); LC-MS (ESI) m/z 291.1 [M+H]+.