Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][C:23]([F:26])([F:25])[F:24])[CH2:9]1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.[CH3:43][CH:44](Cl)[O:45]C(Cl)=O>O1CCCC1>[C:44]([O:27][C@:14]([C@@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][C:23]([F:25])([F:26])[F:24])(=[O:45])[CH3:43]
Reactant: OC(Cc1ccccc1SC(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O[C@@](Cc1ccccc1SC(F)(F)F)(c1ccccc1)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethylsulfanyl-phenyl)-ethanol (218 mg g, 1 equiv.) and solid supported Hunig's base (available from Argonaut, 1 g, 5 equiv.) in dry tetrahydrofuran (4 mL) at 0° C. under nitrogen atmosphere was added ACE-Cl (502 μL, 10 equiv.). The reaction mixture was left to warm to room temperature for 48 hours. All volatiles were evaporated under vacuum, and the resulting solid was taken-up with methanol (50 mL) and stirred at room temperature overnight. The solution was filtered through acid ion exchange column and the required fractions evaporated to dryness. The resulting solid was purified via preparative HPLC to give 62 mg of the title compound as a colourless oil. 1H NMR (300 MHz, CDCl3) δ: 2.01 (s, 3H), 2.43-2.47 (m, 1H), 2.63-2.70 (m, 1H), 2.81-2.94 (m, 2H), 3.24 (d, 1H, J=13.57 Hz), 3.85-3.96 (m, 2H), 4.01-4.05 (m, 1H), 4.09-4.13 (m, 1H), 4.45 (bs, 4H), 6.90-6.93 (m, 1H), 7.13-7.26 (m, 7H), 7.55-7.58 (m, 1H) ppm. LCMS (12 minute method) [M+H]+=384 @ Rt 5.13 min. single peak.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5](=[N:7][OH:8])[NH2:6].Cl.[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.N>>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: O=C(Cl)c1cccnc1
Reactant: NC(=NO)c1ccc(F)c(F)c1
Agent: Cl
Agent: N
Product: Fc1ccc(-c2noc(-c3cccnc3)n2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 1 using 3,4-difluoro-N′-hydroxybenzimidamide (Tyger Scientific) and nicotinoyl chloride hydrochloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.74 (dd, J=7.5, 4.4 Hz, 1H), 8.60 (dt, J=7.8, 2.1 Hz, 1H), 8.93 (dd, J=4.8, 1.6 Hz, 1H), 9.38 (dd, J=2.2, 1.0 Hz, 1H), 9.44-9.48 (m, 3H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]1[CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>O.C(N(CC)CC)C>[NH3:1].[C:9]([N:4]1[CH2:5][CH2:6][NH:1][C@H:2]([CH2:7][OH:8])[CH2:3]1)(=[O:11])[CH3:10]
Reactant: OC[C@@H]1CNCCN1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCN[C@H](CO)C1
Product: N
Temperature: 25 °C
Reaction time: 1 h
Yield: 287.3 %

Procedure:
A solution of (S)-2-piperazinemethanol (1.25 g) in a mixture of water (12 ml) and triethylamine (3.2 ml) at ambient temperature was treated with a solution of acetic anhydride (1.25 ml; 1.32 mmol) in water (25 ml). The mixture was stirred at ambient temperature for 1 h, and anhydrous sodium carbonate (2 g) was added. The solvent was removed in vacuo. The residue was purified by flash column chromatography using dichloromethane:methanol:ammonia, 75:10:2 as eluant to give the title compound as a pale yellow oil (0.6 g).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:62])(=O)=O)=CC=1>C(O)(=O)C.C1COCC1>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@:9]([F:62])([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reaction time: 2 h
Yield: 18.2 %

Procedure:
Erythromycin A (5 g, 6.813 mmole) was dissolved in glacial acetic acid (20 mL) at room temperature and stirred for 2 hours. N-fluorobenzenesulfonimide (2.2 g, 6.813 mmole) dissolved in THF (4 mL) was added and stirring continued for an additional 18 hours at 22° C. The reaction was worked up in the same manner as Example 1 to afford only 0.93 g (7% yield) of crude flurithromycin.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:9]([CH3:15])=[N:10]2)=[O:4].[C:22]([O:26][C:27]([NH:29][C@H:30]([CH3:39])[C:31](=[O:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][CH:30]([CH3:39])[C:31](=[O:38])[CH:32]([CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:9]([CH3:15])=[N:10]2)=[O:4])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: CCOC(=O)CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NCC(F)(F)F)nc12)C(=O)C(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A mixture of 2-bromo-1-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)ethanone (616) (300 mg, 0.83 mmol), ethyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (602) (258 mg, 0.99 mmol) and K2CO3 (286 mg, 2.07 mmol) in DMF (2.75 mL) was stirred at RT for 1 h. The reaction mixture was concentrated. Saturated NH4Cl (aq.) and EtOAc was added and the layers were separated. The aq. layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to provide ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (293a) (285 mg, 64% yield). m/z (ESI, +ve) 541.1 (M+H)+. This material was put into a sealed tube with 2 mL of EtOH. AcOH (1 mL) and NH4OAc (511 mg, 6.63 mmol) were added and the mixture was stirred at 60° C. overnight (21 h). The reaction mixture was concentrated. The residue was put into solution with EtOAc and water. The layers were separated and the organic layer was washed with water, 1 M NaOH (aq.) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to provide ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (293b) (215 mg, 0.41 mmol, 50% yield) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (dt, J=7.53, 0.73 Hz, 1H), 7.29-7.44 (m, 2H), 7.12 (d, J=2.54 Hz, 1H), 5.00 (br. s., 1H), 4.25-4.53 (m, 4H), 2.14-2.30 (m, 2H), 1.64 (s, 3H), 1.58 (d, J=7.24 Hz, 3H), 1.36-1.48 (m, 12H). 19F NMR (377 MHz, CDCl3) δ ppm −70.80. m/z (ESI, +ve) 522.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CC[N:46]([CH:50]([CH3:52])C)[CH:47]([CH3:49])C.N1CCCC1>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:46]4[CH2:47][CH2:49][CH2:52][CH2:50]4)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CN4CCCC4)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.6 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (22 μl, 0.13 mmol) was added pyrrolidine (7.0 μl, 0.08 mmol). The reaction mixture was stirred at RT for 3 hr. LC-MS indicated 50% conversion to product. The reaction mixture was heated to 40° C. and stirred for 12 hr. LC-MS indicated 95% conversion to product. A further portion of pyrolidine (7.0 μl, 0.08 mmol) was added and the reaction mixture continued to stir at 40° C. for 5 hr. LC-MS indicated complete conversion to product. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(pyrrolidin-1-yl)acetamide (Example 8) as a light orange solid (17 mg, 32%): m/z 632 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 1.76 (4H, m), 2.39 (3H, s), 2.62 (4H, m), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.28 (1H, d), 7.34 (2H, d), 7.44 (2H, d), 7.65-7.55 (3H, m), 7.92 (1H, d), 8.36-8.29 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 9.93 (1H, s).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](O)=[O:15].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH2:39][CH2:38]1>O1CCCC1>[ClH:29].[Cl:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[N:37]1[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:14]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:12][C:13]=3[CH:1]=2)=[O:15])[CH2:41][CH2:42]1
Reactant: NCCCCN1CCN(c2cccc(Cl)c2Cl)CC1
Reactant: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cl
Product: O=C(NCCCCN1CCN(c2cccc(Cl)c2Cl)CC1)c1ccc2c(c1)Cc1ccccc1-2
Reaction time: 8 h
Yield: 139.4 %

Procedure:
A mixture of 9H-fluorene-2-carboxylic acid (100 mg, 0.48 mmol) and 1.1'-carbonyldiimidazole (80 mg, 0.5 mmol) in 10 mL of anhydrous tetrahydrofuran was stirred for 8 hours. A solution of 4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-1-aminobutane (150 mg, 0.5 mmol) in 1 mL of tetrahydrofuran was added and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with aqueous Na2CO3 solution, dried (Na2SO4) and concentrated in vacuo to give the title compound (185 mg, 78%). Hydrochloride salt was prepared by treating the free base with a solution of hydrogen chloride in ethyl acetate (mp 262-4° C.).
Reaction SMILES: [F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([S:13][CH3:14])[C:10]2[C:5](=[C:6]([C:15]#[N:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.S(=O)(=O)(O)[OH:26].C(=O)(O)[O-].[Na+]>O>[F:24][C:2]([F:1])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([S:13][CH3:14])[C:10]2[C:5](=[C:6]([C:15]([NH2:16])=[O:26])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C#N)cccc12
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C(N)=O)cccc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carbonitrile from Example 35 step C (200 mg, 0.57 mmol) were added concentrated sulfuric acid (2.88 mL) and water (0.32 mL). The mixture was stirred at 65° C. for 1 h and then allowed to cool to rt. The mixture was neutralized by slow addition of saturated aq sodium bicarbonate and then extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carboxamide (191 mg, 92%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.60 (s, 3H) 7.89-8.15 (m, 4H) 8.36-8.44 (m, 1H) 8.62-8.69 (m, 1H) 8.71-8.79 (m, 1H) 9.28-9.39 (m, 1H).
Reaction SMILES: C([Li])CCC.C(OCC)C.Br[C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.CN[C:24](=[O:30])[CH:25](OC)[CH2:26][CH3:27]>C1COCC1>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([C:24](=[O:30])[CH2:25][CH2:26][CH3:27])[CH:13]=1
Reactant: CCC(OC)C(=O)NC
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(=O)c1cnc2ccccc2c1
Temperature: 0 °C
Yield: 58.1 %

Procedure:
In a dry 3-necked flask under argon at -50° C., n-butyl lithium (0.0025 M, 0.021 ml) was added to 150 ml diethylether. Then 4.16 grams 3-bromoquinoline in 2 ml THF was added dropwise while stirring and maintaining the temperature at -60° C. to -55° C. The solution was stirred for 30 minutes, and 2.3 grams N-methyl-methoxybutyramide were then added dropwise at -50° C. and the solution was stirred an additional 30 minutes. The solution was then allowed to warm to 0° C. and stirred for one hour. The reaction was quenched with a saturated solution of ammonium chloride and the THF layer separated, washed with brine, separated, and dried over magnesium sulfate. Filtration through diatomaceous earth, followed by concentration and subsequent thin layer chromatography (35% ethylacetate/65% CH2Cl2) gave a total yield of 2.03 g (51%) of the title compound.
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[NH2:11].CO[C:15]1C(OC)=C[C:18]2[NH:19][C:20](CCCNC)=N[C:17]=2[CH:16]=1>>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:11]=[C:15]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Reactant: COC(=O)c1cccc(N)c1N
Product: CNCCCc1nc2c(C(=O)OC)cccc2[nH]1

Procedure:
Prepared from 2,3-diamino-benzoic acid methyl ester (J. Med. Chem. 2000, 43(22), 4084-4097) in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][N:11]=1.[P:18]([O:23]C)([O:21][CH3:22])[O:19][CH3:20]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][P:18]([O:21][CH3:22])([O:19][CH3:20])=[O:23])=[CH:12][N:11]=1
Reactant: BrCc1ccc(-c2nc3ccccc3s2)nc1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc(-c2nc3ccccc3s2)nc1)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
1.5 g (0.0049 mol) of 2-(benzothiazol-2-yl)-5-bromomethylpyridine was reacted with 3 ml of trimethyl phosphite in nitrogen gas streams at 130°-160° C. for 15 minutes. The reaction mixture was allowed to cool down to room temperature and the resulting crystals were recrystallized from ethyl acetate. By the above procedure was obtained 1.1 g (70%) of 2-(benzothiazol-2-yl)-5-dimethoxyphosphinylmethylpyridine as colorless needles, m.p. 151.5°-152.5° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH3:18][C:19]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[N:34][O:35][CH3:36])[C:30](OC)=[O:31].ClCCl>CO>[CH3:18][C:19]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[N:34][O:35][CH3:36])[CH:30]=[O:31]
Reactant: CON=C(C(=O)OC)c1ccccc1COc1cc(C)ccc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CON=C(C=O)c1ccccc1COc1cc(C)ccc1C
Reaction time: 3 h

Procedure:
1M diisobutylaluminum hydride/toluene solution (5.5 ml, 5.5 mmol) was added dropwise to a mixture of methyl 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetate (1.64 g, 5 mmol) and dichloromethane (15 ml) at -70° C. over 0.5 hours, and then the mixture was stirred at -70° C. to room temperature for 3 hours. Methanol (3 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated insoluble materials were removed, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetaldehyde (0.54 g, 36.3%) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=O)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].O>O1CCOCC1.C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[S:21])=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1ccccn1-c1ccc(I)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: S=c1ccccn1-c1ccc(I)cc1
Temperature: 80 °C

Procedure:
A mixture of 1-(4-iodophenyl)pyridin-2(1H)-one prepared above (0.760 g, 2.56 mmol), NaHCO3 (2.15 g, 25.6 mmol) and P2S5 (2.27 g, 10.2 mmol) in dioxane (20 mL) was heated at 80° C. overnight. After being cooled to room temperature, water and CH2Cl2 were added. The organic layer was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give 1-(4-iodophenyl)pyridine-2(1H)-thione as a solid (0.752 g). MS 313.8 (M+H).
Reaction SMILES: [OH-].[Na+].O1CCCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][C:23]1[C:32]([F:33])=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([Cl:34])[N:24]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CO>[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][C:23]1[C:32]([F:33])=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([Cl:34])[N:24]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c(C(=O)O)cc1F
Temperature: 65 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
A 1N sodium hydroxide aqueous solution (15 ml) was added to a solution of tetrahydrofuran (30 ml) and methanol (30 ml) containing methyl 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinate (3.00 g), followed by stirring at 65° C. for 2 hours. The reaction mixture was cooled to room temperature, the solvent was distilled away under reduced pressure, and a saturated aqueous ammonium chloride solution, tetrahydrofuran, and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Colorless oily matter of 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinic acid (3.00 g) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40])=[O:32]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:31](=[O:32])[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1Cl
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Oc1ccccc1Cl

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-chlorophenyl chloroformate according to the procedure of Example 65. MS (ES) m/z 546.9.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.O.O.[Cl:21][Sn]Cl>O.Cl>[ClH:21].[NH:5]([C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1)[NH2:1]
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Reactant: Nc1ccc(C(=O)O)c2c1CCCC2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(C(=O)O)c2c1CCCC2
Temperature: -5 °C
Yield: 73.3 %

Procedure:
A solution of 0.26 g of NaNO2 in 1 ml of water is added to a solution, cooled to -5° C., of 0.73 g of 4-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid in 10 ml of concentrated HCl. After one and a half hours of stirring at -5° C., a solution of 3.4 g of SnCl2.2H2O in 34 ml of concentrated HCl is added at -5° C. The mixture is stirred for 1 hour at RT and filtered, and the product is washed with concentrated HCl and dried under a stream of dry nitrogen to obtain 0.67 g of the expected hydrazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[OH:12][CH2:13][C:14]([CH3:18])([CH2:16]O)[CH3:15]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:12][CH2:13][C:14]([CH3:18])([CH3:16])[CH2:15][O:6]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CC(C)(CO)CO
Solvent: Cc1ccccc1
Product: COc1ccc(C2OCC(C)(C)CO2)cc1Br

Procedure:
3-Bromo-4-methoxybenzaldehyde (60.0 g, 279 mmol) was dissolved in toluene (600 ml) and, after addition of neopentyl glycol (32.0 g, 306 mmol) and Amberlyst 15 (3.6 g), the reaction mixture was heated under reflux with a water trap for 2 h. After cooling, the reaction mixture was filtered, washed twice with water and then concentrated under reduced pressure. The remaining oil was mixed with heptane, whereupon the product precipitates and was filtered off and washed with heptane. Yield: 57.3 g (68% of theory).