Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:33].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15][C:16]([Cl:33])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: ClCCl
Solvent: CO
Product: CCCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1

Procedure:
Subsequent chlorination (70° C.; 3h30) of 3-propyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (2.940 g; 6.720 mmol), and purification by FC (DCM/MeOH=25/1) afforded 1-chloro-3-propyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (1.550 g; 49%). LC-MS: tR=1.09 min.; [M+H]+=472.00 g/mol.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[C:7]([CH2:16]O)=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>C(OCC)C>[Br:5][C:6]1[C:7]([CH2:16][Br:2])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: BrP(Br)Br
Reactant: OCc1cc2ccccc2cc1Br
Solvent: CCOCC
Product: BrCc1cc2ccccc2cc1Br
Reaction time: 1 h

Procedure:
PBr3 (3.7 mL, 0.039 mol) was added dropwise to a suspension of 3-bromo-2-naphthalenyl methanol (8.55 g, 0.036 mol) and diethyl ether (80 mL) at 0° C. After 1 hour, the reaction was concentrated and partitioned between CH2Cl2 and H2O. The organic layer was separated and dried over MgSO4. Concentration in vacuo afforded 3-bromo-2-bromomethylnaphthalene as a crude product (10.6 g). The crude product was flash chromatographed on silica gel to afford the pure product as an off-white powder (6.0 g, m.p. 110°-111° C., yield 56%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48](O)=O)=[CH:44][CH:43]=2)[CH2:38][CH2:37]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:48][C:45]1[CH:44]=[CH:43][C:42]([CH:39]2[CH2:40][CH2:41][N:36]([CH3:34])[CH2:37][CH2:38]2)=[CH:47][CH:46]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCNc1ccc(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1ccc(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 78.7 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-5-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg) according to an analogous synthetic method to Example 337 described below, the title compound (50 mg) was obtained.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])=[CH:7][CH:6]=1)([O-])=O.[H][H]>[C].[Pd].CO>[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@@H:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[OH:16])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(CCNC[C@H](O)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(CCNC[C@H](O)c2ccccc2)cc1
Temperature: 20 °C
Yield: 94.5 %

Procedure:
A mixture of 11.0 kg of (R)-2-[[2-(4-nitrophenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 110 liters of methanol and 1.20 kg of wet 10% palladium-carbon (wetting rate: 54.2%) was stirred in a hydrogen atmosphere until absorption of hydrogen stopped. The reaction solution was filtered and the filtrate was concentrated in vacuo. Methanol (40 liters) was added to the residue to dissolve at 40° C. and crystallization was conducted by addition of 220 liters of diisopropyl ether thereto followed by stirring at 20° C. throughout one night. The crystals were filtered and washed with 30 liters of diisopropyl ether. They were dried in vacuo to give 9.43 kg of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:23]4=[O:29])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][OH:33].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:31][CH2:32][OH:33])[C:23]4=[O:29])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(-n3cccc(O)c3=O)cc2)cn1)c1ccc(Cl)s1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3cccc(OCCO)c3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
A mixture of 5-chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (30 mg, 0.070 mmol), 2-bromoethanol (0.020 mL, 0.28 mmol) and Cs2CO3 (90 mg, 0.28 mmol) in DMSO (1 mL) was stirred at 60° C. for 1 h. It was then purified by HPLC to give the titled compound (5 mg). MS 471.0 and 473.0 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([CH2:41][CH3:42])([C:37]([O:39]C)=[O:38])[CH2:35][CH3:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[Li+].[OH-].O>CO>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:9]3([CH:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:33][C:34]([CH2:41][CH3:42])([C:37]([OH:39])=[O:38])[CH2:35][CH3:36])[CH2:13][C:12](=[O:14])[NH:11][CH:10]3[C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 40 °C
Yield: 51.1 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-4′-[5-chloro-2-(1-ethyl-1-methoxycarbonyl-propoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.159 mmol), LiOH (19.87 mg, 0.8 mmol), H2O (2 mL) and methanol (3 mL) was heated at 40° C. for 4 h. Then methanol was removed by vacuum. The aqueous solution was acidified to “PH” 1-2 by addition of concentrated hydrochloride acid. The precipitate was collected by filtration and purified by Prep-HPLC to give the title compound as a white solid (50 mg).
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1>C(OC(C)C)(C)C>[CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: CC(C)OC(C)C
Product: O=C(O)CCCCC1CCSS1
Temperature: -7.5 °C
Yield: 81.3 %

Procedure:
A solution which contained 16.6 g R-(+)-thioctic acid and 3.4 g S-(-)-thioctic acid in 80 ml diisopropyl ether was cooled off from 35 to 40° C. down to -5 to -10° C., filtered and dried. 13.5 g thioctic acid were obtained in the novel modification as first crystallizate. The R-(+)thioctic acid content was 78.8% with a melting range of 48 to 54° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.[ClH:20]>C(OCC)C>[ClH:20].[CH2:1]([NH:5][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of isobutylamine (0.90 mL, 0.0091 mol), bromoacetic acid, ethyl ester (1.0 mL, 0.0090 mol), and triethylamine (1.28 mL, 0.00918 mol) in diethylether (15 mL) was stirred at room temperature for 24 hours. The resulting suspension was filtered off and washed with diethylether. The filtrate and washings were combined and rotary evaporated to an oil. The oil was chromatographed on silica gel (150 g, 230-400 mesh) eluting with dichloromethane-diethylether (19:1, 8×125 mL; 15:1, 7×125 mL; 10:1, 15×125 mL). Fractions containing product were combined and rotary evaporated to give an oil. The oil was dissolved in diethylether, concentrated hydrochloric acid (0.52 mL, 0.0063 mol HCl) was added, and the volatiles were rotary evaporated to give a white solid. The solid was dried in vacuo; yield 1.0 g (59%).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35]1[C:40]([F:41])=[CH:39][C:38]([F:42])=[CH:37][C:36]=1[CH2:43][CH2:44]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]1[C:36]([CH2:43][CH2:44][I:25])=[CH:37][C:38]([F:42])=[CH:39][C:40]=1[F:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCCc1cc(F)cc(F)c1OCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(F)c(OCc2ccccc2)c(CCI)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
A solution of Ph3P (750 mg, 2.86 mmol) and imidazole (195 mg, 2.86 mmol) in DCM (15 mL) was cooled to 0° C. Added to this was iodine (726 mg, 2.86 mmol) and the resulting mixture was stirred at 0° C. for 30 min. Then, 2-(2-(benzyloxy)-3,5-difluorophenyl)ethanol (630 mg, 2.384 mmol) was added portionwise over several minutes and the resulting mixture was stirred at room temp. After 5 h, the mixture was filtered washing the solids with DCM. The filtrate was washed with aq Na2S2O3 and the organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (5%-30% EtOAc/hexane) to give 2-(benzyloxy)-1,5-difluoro-3-(2-iodoethyl)benzene (630 mg, 1.684 mmol, 70.6% yield) as light yellow viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.46-7.34 (m, 5H), 6.83 (ddd, J=11.3, 8.2, 3.0 Hz, 1H), 6.69 (dt, J=8.6, 2.3 Hz, 1H), 5.10 (s, 2H), 3.21 (d, J=7.7 Hz, 2H), 3.13-3.00 (m, 2H).
Reaction SMILES: [OH:1][C:2]([P:15](=[O:18])([OH:17])[OH:16])([P:11](=[O:14])([OH:13])[OH:12])[CH2:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.I[CH3:20]>[OH-].[Na+].O.C(O)C>[OH-:1].[OH:1][C:2]([P:15]([OH:16])([OH:17])=[O:18])([P:11]([OH:12])([OH:13])=[O:14])[CH2:3][CH2:4][C:5]1[CH:6]=[N+:7]([CH3:20])[CH:8]=[CH:9][CH:10]=1
Reactant: O=P(O)(O)C(O)(CCc1cccnc1)P(=O)(O)O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[n+]1cccc(CCC(O)(P(=O)(O)O)P(=O)(O)O)c1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
[1-Hydroxy-3-(3-pyridinyl)propylidene]bis[phosphonic acid](3.37 mmol, 1.0 g) is dissolved in 8.4 ml of 1N NaOH solution with 29 ml of distilled water. Iodomethane (16.83 mmol, 1.05 ml) is added in 19 ml of ethanol. This reaction mixture is heated at 80° C. overnight. The solvent is evaporated in vacuo and the residue is triturated with acetone then recrystallized from ethanol and water to yield 0.5 g of 3-(3-hydroxy-3,3-diphosphono-propyl)-1-methyl pyridinium hydroxide, inner salt.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH3:15])[C:6]=1[CH3:26].CO.[OH-].[Li+]>C1COCC1>[CH3:25][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH:14]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[C:6]2[CH3:26])[CH3:15])=[CH:17][CH:18]=1)(=[O:23])=[O:24]
Reactant: COC(=O)Cc1c(C)n(C(C)c2ccc(S(C)(=O)=O)cc2)c2ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cccnc2n1C(C)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {1-[1-(4-methanesulfonyl-phenyl)-ethyl]-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-acetic acid methyl ester (Enantiomer A) (22 mg, 0.05 mmol) in THF (0.5 ml) and methanol (0.5 ml) is treated with 2M lithium hydroxide (0.2 ml) and stirred at room temperature for 30 minutes. The solvent is removed in vacuo and the crude is dissolved in water (10 ml) and acidified to pH1 using concentrated HCl. The mixture is then extracted with ethyl acetate (2×10 ml) and the organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo to yield the titled product as a colourless glassy solid. (MH+ 373) The enantiomer of the titled compound (Enantiomer 2) is prepared analogously using the procedure described above by replacing Enantiomer A with Enantiomer B. (MH+373)
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]([OH:13])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22]>>[F:14][C:15]1[CH:16]=[C:17]([C:2]2[C:3]3[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]([OH:13])[C:4]=3[CH:5]=[N:6][CH:7]=2)[CH:18]=[CH:19][C:20]=1[C:21]([F:22])([F:23])[F:24]
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: CC1(C)Cc2c(Br)cncc2C1O
Product: CC1(C)Cc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc2C1O

Procedure:
In analogy to the procedure described for the preparation of examples 85 and 86, 4-bromo-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (intermediate A-17) and 3-fluoro-4-trifluoromethyl-phenylboronic acid gave racemic 4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,6-dimethyl-5,7-dihydrocyclopenta[c]pyridin-7-ol. SFC separation afforded (+)-(7R)-4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,6-dimethyl-5,7-dihydrocyclopenta[c]pyridin-7-ol (example 108) and (−)-(7S)-4-[3-fluoro-4-(trifluoromethyl)phenyl]-6,6-dimethyl-5,7-dihydrocyclopenta[c]-pyridin-7-ol (example 109) as white solids. MS: 309.0 (M+H+).
Reaction SMILES: [C:1]1([NH:7][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.I[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].ClC1C=CC=CC=1Cl>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(I)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 81.4 %

Procedure:
4.5 g (27 mmol) of diphenylamine, 11.0 g (51 mmol) of p-iodotoluene, 5.5 g (40 mmol) of anhydrous potassium carbonate, and 1.1 g of copper chips were added to 30 mL of o-dichlorobenzene. The mixture was subjected to heating and refluxing for 7 hours under stirring conditions. Upon completion of the reaction, the reaction solution was filtered, the filtrate was washed with a 3-5% aqueous solution of sodium thiosulfate, and then with saturated brine. After drying the organic layer with anhydrous sodium sulfate, the solvent was removed. The reaction mixture obtained was recrystallized with ethanol, and 4-methyltriphenylamine was obtained in an amount of 5.7 g (yield 81.4 %).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)=[CH2:2].[CH2:11]([P:18]([O:22][CH3:23])(=[O:21])[O:19][CH3:20])[P:12]([O:16][CH3:17])(=[O:15])[O:13][CH3:14]>>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:11]([P:12]([O:13][CH3:14])(=[O:15])[O:16][CH3:17])[P:18]([O:22][CH3:23])(=[O:21])[O:19][CH3:20])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: COP(=O)(CP(=O)(OC)OC)OC
Product: C=Cc1ccc(CC(P(=O)(OC)OC)P(=O)(OC)OC)cc1

Procedure:
Following the General Synthetic Procedure B, 4-vinylbenzylchloride is reacted with tetramethyl methanebisphosphonate to produce tetramethyl 4-vinylbenzyl-methanebisphosphonate that is then hydrolyzed to yield 4-vinylbenzyl-methanebisphosphonic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=1)[CH2:6][CH2:5]2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Oc1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CCc2cc(O)ccc2C1
Reaction time: 8 h

Procedure:
1.2 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline are suspended in 50 ml of methylene chloride, 1.2 ml of triethylamine are added, and a solution of 1.4 g of 4-chlorobenzoyl chloride in 10 ml of methylene chloride is added dropwise with stirring and cooling. After standing overnight, the mixture is extracted by shaking with 2N hydrochloric acid and water, and the organic phase is dried and evaporated in a rotary evaporator. A colorless oil remains, and this crystallizes on trituration with ethyl acetate.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11](NS(C3C=CC4C(=CC=CC=4)C=3)(=O)=O)[CH:12]=2)[CH2:7]1)[CH3:4].[CH2:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][OH:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[ClH:1].[CH3:4][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:45][CH2:44][C:41]3[CH:40]=[CH:39][C:38]([C:35]4[CH:36]=[CH:37][C:32]([CH2:30][CH3:31])=[CH:33][CH:34]=4)=[CH:43][CH:42]=3)[CH:12]=2)[CH2:7]1)[CH3:2]
Reactant: CN(C)CC1CCc2cc(NS(=O)(=O)c3ccc4ccccc4c3)ccc2C1
Reactant: CCc1ccc(-c2ccc(CO)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(COc3ccc4c(c3)CCC(CN(C)C)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(N,N-Dimethylamino)methyl-6-hydroxytetralin (300 mg; obtained in Reference Example 16), (4′-ethylbiphenyl-4-yl)methanol (372 mg) and triphenylphosphine (460 mg) were dissolved in THF (5 ml), to which was dropwise added diethyl azodicarboxylate (305 mg) with cooling with ice. The reaction mixture was stirred at room temperature for 4 hours, and then the solvent was evaporated out. Water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/10), and then processed with a solution of 4 N hydrochloric acid-ethyl acetate to form a hydrochloride. The thus-formed salt was recrystallized from ethanol-diisopropyl ether to obtain the entitled compound (310 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].Cl.Cl.[OH:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:30]4[CH2:31][CH2:32][N:27]([OH:26])[CH2:28][CH2:29]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: ON1CCNCC1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCN(O)CC4)c(F)cc3cc2c1=O
Yield: 86.1 %

Procedure:
3-Ethoxycarbonyl-7-fluoro-8-(4-hydroxy-1-piperazinyl)-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8 ]naphthyridine (3 g), 1-hydroxypiperazine dihydrochloride (1.97 g) and sodium carbonate (1.99 g). 3-Ethoxycarbonyl-7-fluoro-8-(4-hydroxy-1-piperazinyl)-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (3.25 g) is obtained in the form of a yellow solid, m.p. 258°-260° C.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1>>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)[CH:10]=1
Reactant: O=C1C=C(Br)CCC1
Reactant: OB(O)c1cccnc1
Product: O=C1C=C(c2cccnc2)CCC1
Yield: 54 %

Procedure:
Prepared as described above from 3-bromocyclohex-2-enone and 3-pyridinylboronic acid. Purification by automated flash chromatography using gradient elution (20 to 60% ethyl acetate/hexanes) yielded the product (42 mg, 54%) as a dark orange solid. 1H NMR (300 MHz, CDCl3): δ 7.80 (ddd, J=7.8, 2.4, 1.5 Hz, 1H), 7.34 (ddd, J=7.8, 4.5, 0.6 Hz, 1H), 6.41 (t, J=1.5 Hz, 1H), 2.78 (t, J=5.8 Hz, 2H), 2.51 (t, J=6.6 Hz, 2H), 2.19 (quintet, J=6.2 Hz, 2H). 13C (75 MHz, CDCl3): 199.2, 156.5, 150.8, 147.3, 133.4, 126.6, 123.6, 37.4, 28.0, 22.9. LCMS (ESI): mass calcd for (C11H11NO) m/z 173.08; measured [M+H]+: m/z 174.16.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])OC(=O)[NH:9][C:4]=2[CH:3]=1.Cl.[CH3:15][O:16][NH2:17].[OH-].[Na+]>CCOC(C)=O>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:13]=[CH:12][C:5]=1[C:6]([NH:17][O:16][CH3:15])=[O:11]
Reactant: CON
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CONC(=O)c1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
NMR Spectrum: (DMSO-d6) 6.88 (dd, 1H), 7.21 (ddd, 1H), 8.00 (dd, 1H), 11.87 (s, 1H). 7-fluoro-1H-3,1-benzoxazine-2,4-dione (0.85 g, 4.69 mmol) was added to stirred solution of O-methylhydroxylamine hydrochloride (1.960 g, 23.47 mmol) in a 2N aqueous solution of sodium hydroxide (11.73 ml, 23.47 mmol) at 25° C. The resulting solution was stirred at room temperature for 2 hours. The solution was diluted with EtOAc, washed sequentially with water and brine. The organic layer was dried over magnesium sulfate and evaporated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM to afford 2-amino-4-fluoro-N-methoxybenzamide (0.390 g, 45.1%) as a white crystalline solid. NMR Spectrum: (DMSOd6) 3.67 (s, 3H), 6.30 (dd, 1H), 6.47 (ddd, 1H), 6.62 (bs, 2H), 7.37 (dd, 1H), 11.40 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:24]2=[O:25])=[CH:4][CH:3]=1
Reactant: O=C(NNc1ccc(Cl)cc1)c1cccs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1oc(-c2cccs2)nn1-c1ccc(Cl)cc1
Yield: 81.6 %

Procedure:
A mixture of N′-(4-chlorophenyl)thiophene-2-carbohydrazide (20 g, 79.3 mmol), triethylamine (10 mL) and carbonyldiimidazole (16.2 g, 100 mmol) was refluxed in THF (100 mL) for 1 hour. The crude product obtained after the removal of the solvent was triturated with water, filtered, and dried, followed by recrystallization from ethyl acetate/hexanes to provide 3-(4-chloro-phenyl)-5-(thiophene-2-yl)-1,3,4-oxadiazol-2(3H)-one (18 g, 64.7 mmol, yield 81%). The HPLC purity of the final product was 99.9%. LC-MS [M+H] 279.9 (C12H7ClN2O2S+H, expected 279.72). The 1H-NMR spectrum was in accordance with the chemical structure.