Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18](OCC)=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[O:24][CH3:25].Cl.[NH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CCN(C(C)C)C(C)C>O1CCOCC1>[Br:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18]([NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: CCOC(=O)C1=C(O)c2cc(OC)c(Br)cc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1Br)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 95 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A mixture of ethyl 7-bromo-4-hydroxy-6-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.28 g, 0.68 mmol) and tert-butyl 2-aminoacetate hydrochloride (0.17 g, 1.0 mmol) in 5 mL dioxane was treated with DIPEA (0.26 g, 2.0 mmol). The mixture was warmed to 95° C. and stirred for 3 hours, M+1=496/498. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.28 g of the title compound as a white yellow solid. MS m/e=496/498 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=2)=[CH:3][CH:4]=1)=[O:13]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Temperature: 80 °C

Procedure:
To a solution of 4-hydroxynaphthaldehyde (1.24 g, 7.2 mmol) in DMSO (8 mL) was added 2-chloro-5-cyanopyridine (1.0 g, 7.2 mmol) and K2CO3 (2.0 g, 14.5 mmol). The reaction was heated at 80° C. for 4 h. The reaction was cooled to rt and poured into water (100 mL). The resulting solid was filtered, washed with water, ether and air dried to give the title compound: RT=3.54 min; m/z (ES+)=275.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[CH:16][C:3]=12.[Br:17]Br.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:17][C:16]1[C:3]2[C:4](=[N:5][N:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]=2[Cl:1])[NH:14][N:15]=1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]ncc12
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Clc1c(-c2ccccc2)nnc2[nH]nc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A mixture of 4-chloro-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (155 mg, 0.67 mmol), bromine (51 μL, 1 mmol) and triethylamine (98 μL, 0.7 mmol) in chloroform (4 mL) was stirred at room temperature for 1 h. Additional bromine (25 μL) and chloroform (4 mL) were added and the reaction mixture was stirred at room temperature for 4 h. Further bromine (25 μL) and triethylamine (98 μL) were added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 and a sodium bicarbonate solution. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were dried (phase separator cartridge) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, ethyl acetate/isohexane 0:1 to 1:1), to provide Compound Ibb as a solid (97 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[N-:11]=[N+:12]=[N-:13].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(C)(C)C>[N:11]([CH2:4][C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10])=[N+:12]=[N-:13]
Reactant: Fc1cccc(F)c1CBr
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: [N-]=[N+]=NCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 2,6-diflourobenzyl bromide (100 gms), tetrabutylammonium bromide (10 gms), t-butanol (200 ml) and sodium azide (62.8 gm) were stirred at room temperature for 22-24 hours. After the completion, reaction mass was filtered and washed with t-butanol (2.5 ml ) to give 2-(azidomethyl)-1,3-difluorobenzene.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C@H:8]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)(=O)=O.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:16]2[CH:17]=[CH:18][C:13]([N:9]3[C@@H:8]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)[C@H:7]([CH2:6][S:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:11][C:10]3=[O:12])=[CH:14][CH:15]=2)=[CH:21][CH:22]=1
Reactant: Sc1ccccc1
Reactant: CS(=O)(=O)OC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1cccc(F)c1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](CSc2ccccc2)[C@H](c2cccc(F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 75 °C

Procedure:
((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate (0.3 mmol, prepared by the methods described in example 34) was dissolved in ethanol (1.5 mL) and treated with benzenethiol (0.6 mmol) and triethylamine (0.6 mmol). The reaction mixture was heated to 75° C. for 8 h, then was cooled to room temperature, diluted with ethyl acetate, washed with 1M HCl and then purified on silica gel (10-30% ethyl acetate/hexanes) to give the title compound as a colorless oil. 1H NMR (CDCl3) δ (ppm) 7.31-7.37 (m, 5H), 7.24-7.29 (m, 5H), 7.08 (d, 1H, J=7.7 Hz), 6.97-7.04 (m, 2H), 6.86-6.91 (m, 4H), 5.21 (d, 1H, J=4.0 Hz), (ddd, 1H, J=8.4, 4.0, 4.0 Hz), 3.46 (dd, 1H, J=14.2, 3.9 Hz), 3.22 (dd, 1H, J=14.2, 8.7 Hz). HPLC-MS calculated C28H21ClFNO3S (M+H+): 506.1, found 506.1.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])CCCC[CH2:2]1.N1(C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)C[C@H](O)C[C@H]1C(O)=[O:49]>>[CH:38]1([N:19]2[C:18]3[CH:44]=[CH:45][C:15]([C:13]([N:12]4[CH2:2][CH:1]([OH:49])[CH2:7][CH:8]4[C:9]([OH:11])=[O:10])=[O:14])=[CH:16][C:17]=3[N:21]=[C:20]2[C:22]2[CH:31]=[C:30]3[C:29](=[CH:24][CH:23]=2)[N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[N:25]3)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Product: O=C(O)C1CC(O)CN1C(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 50 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-Hyp Wang resin (143 mg, 0.7 mmol/g), producing 23 mg of the title compound (50% yield). MS: 560.23 (M−H+) HPLC Procedure A, retention time=11.58 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccc(Cl)nc1
Agent: CC(C)(C)O[K]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(OC)cn2)CC1
Temperature: 120 °C
Yield: 24 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid ethyl ester (0.52 g, 3.34 mmol) and 2-chloro-5-methoxy-pyridine in 10 mL of toluene was added (13 mg, 0.057 mmol) of Pd(II) acetate, (17 mg, 0.027 mmol) of BINAP and tBuOK (0.44 g, 3.90 mmol). The mixture was heated at 120° C. for two hours, concentrated under vacuo and the residue was directly purified on column chromatography (SiO2, EtOAc/Hept 1:2) yielding 0.17 g (24%) of the title compound as a light yellow oil. ES-MS m/e: 265.3 (M-41′).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:31][N:30]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:31][N:30]=1
Reactant: NCc1ccc(CSC2CCCC2)cn1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(CSC4CCCC4)cn3)c2CC1)C(F)(F)F
Yield: 58.9 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (245 mg, 0.58 mmol) with 2-aminomethyl-5-cyclopentylthiomethyl-pyridine (230 mg, 1 mmol) in toluene (5 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/THF (49:1 to 7:3 gradient) to obtain 7-chloro-6-[(5-cyclopentylthiomethyl-pyridin-2-ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (170 mg, 59%). MS (ES+) m/z: 498.1 (M+H)+.
Reaction SMILES: O.[OH-].[Ba+2].[OH-].C(O)C.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[O:18][CH2:19][CH2:20][NH:21]C(=O)C>C(OCC)(=O)C>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[O:18][CH2:19][CH2:20][NH2:21]
Reactant: CC(=O)NCCOc1ccc2ccccc2c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: NCCOc1ccc2ccccc2c1
Temperature: 50 °C
Yield: 103.2 %

Procedure:
A 3-neck round bottom flask was charged with water (50 mL) and barium hydroxide (12.27 g, 71.61 mmol) while stirring. The resulting slurry was charged with ethanol (50 mL) and finally N-(2-(naphthalen-2-yloxy)ethyl)acetamide (10.0 g, 35.80 mmol) as prepared above. The resulting mixture was heated to reflux for 18 h. The reaction was monitored by TLC. The reaction was then allowed to cool to 50° C., then charged with water (50 mL) followed by ethyl acetate (100 mL). The mixture was then stirred for 15 min. The mixture was then filtered and thelayers were separated. The upper organic layer was washed with saturated sodium chloride (50 mL) and dried over sodium sulfate and concentrate to afford 2-(2-naphthyloxy)ethylamine as an amber oil (6.92 g, 47%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].[NH2:43][C:44]1[C:45]([Cl:55])=[CH:46][C:47](Br)=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([C:47]3[CH:46]=[C:45]([Cl:55])[C:44]([NH2:43])=[CH:49][C:48]=3[C:50]([F:52])([F:53])[F:51])=[CH:31][CH:32]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(N)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
Potassium carbonate (280 mg, 2.0 mmol) was added to a solution of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (200 mg, 0.40 mmol) and 5-amino-2-bromo-4-chlorobenzotrifluoride (110 mg, 0.40 mmol; Preparation 51) dissolved in toluene (1.3 mL) and water (0.43 mL). The reaction mixture was sparged under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (56 mg, 0.48 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. for 4 h. The reaction mixture was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce a red solid, which was purified by silica gel chromatography (0-100% ethyl acetate:hexanes) to produce the desired product as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[CH3:18][C:19]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][N:26]=2)[CH2:21][CH2:20]1.CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:28]2[CH:27]=[N:26][C:25]([N:22]3[CH2:23][CH2:24][C:19]([CH3:18])([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:20][CH2:21]3)=[N:30][CH:29]=2)[CH:3]=1
Reactant: CCOC(=O)C1(C)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CCNC(=O)Nc1nc2cc(I)cc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Temperature: 80 °C
Yield: 41.2 %

Procedure:
To a solution of Intermediate 3 (22.7 g, 53.2 mmol) and iv (20 g, 53.2 mmol) in 1,4-dioxane:MeOH (300:180 mL) was added potassium phosphate (17 g, 79 mmol) at RT. The resulting mixture was degassed for 15-20 min by purging N2 followed by the addition of Pd(PPh3)4 (6.1 g, 5.32 mmol). The reaction mixture was again degassed for another 15-20 min and then heated up to 80° C. for 5 h. The reaction mixture was cooled to RT, diluted with EtOAc (500 mL) and passed through celite bed. The filtrate was evaporated and the crude residue was purified by chromatography on silica eluting with 1.5% MeOH:DCM to obtain Intermediate 7 (12 g, 41%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=2[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1.[N:21]1[CH:22]=[CH:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][C:25]=12>>[OH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]3[CH2:28][CH2:29][N:24]4[CH:23]=[CH:22][N:21]=[C:25]4[CH2:26]3)[C:12]=2[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1
Reactant: c1cn2c(n1)CNCC2
Reactant: O=C(O)c1cn(CCO)c2c(F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(CCO)c2c(F)c(N3CCn4ccnc4C3)c(F)cc2c1=O

Procedure:
Using 1-(2-hydroxyethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, the same procedure as in Production Example 1 was followed to yield the title compound.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:12]2=[O:15])=[CH:7][CH:6]=1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:12]2([OH:15])[CH3:1])=[CH:7][CH:6]=1
Reactant: O=C1c2cc(Br)ccc2CCC1Cc1cccnc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)c2cc(Br)ccc2CCC1Cc1cccnc1
Reaction time: 10 h

Procedure:
Methyl magnesium bromide (15 ml of a 3M solution in ether was added dropwise over 5 minutes to a stirred solution of 7-bromo-2-(3-pyridylmethyl)-1-tetralone (3.20 g) in dry tetrahydrofuran (50 ml). The resulting mixture was heated under reflux with stirring for 10 hours and then cooled. An excess of aqueous ammonium chloride solution was added and the mixture was extracted several times with ether. The combined ethereal extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel. Elution with chloroform gave 7-bromo-1-hydroxy-1-methyl-2-(3-pyridylmethyl)-1,2,3,4-tetrahydronaphthalene (2.87 g) as a mixture of isomers which was used directly in the next stage.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[C:5](=[CH:10][C:11]([N:14]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[C:5](=[CH:10][C:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N(Cc2ccccc2)c2ccccc2[N+](=O)[O-])cc1C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(Cc2ccccc2)c2ccccc2N)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A clear solution of stannous chloride dihydrate (0.84 g, 3.72 mmol) in DMF (4ml) was added to a solution of 4-[benzyl-(2-nitrophenyl)amino]phthalic acid dimethyl ester (195 mg, 0.47 mmol) in DMF (4ml) and stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate (2×25 ml). The collected organic phases was washed with water (3×25 ml), dried over magnesium sulphate, and evaporated to dryness in vacuo to give 4-[(2-aminophenyl)benzylamino]phthalic acid dimethyl ester as a slightly coloured oil (yield: 180 mg (100%)).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C(N(CC)CC)C.[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17](Cl)=[O:18]>C(#N)C>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17]([NH:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1)=[O:18]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cc[nH]n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a stirred solution of 3-aminopyrazole (60 g, 0.722 mol, ABCR) in acetonitrile (500 ml) at 0° C. (ice/brine bath) was added, dropwise, triethylamine (201 ml, 1.44 mol) at such a rate to keep the temperature below 5° C. The reaction mixture was stirred at 0° C. for 0.5 h then a solution of 2,6-difluorobenzoyl chloride (127.5 g, 0.722 mol, Aldrich) in acetonitrile (200 ml) was added over approximately 1 h, keeping the temperature between 0-7° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water (250 ml) and EtOAc (500 ml). Some solid formed at the interface, this was filtered off and turned out to be product—combined with isolated product at the end for drying. The aqueous layer was separated and extracted with EtOAc (2×500 ml). The combined organics were washed with water (500 ml), dried (MgSO4), charcoaled, filtered and concentrated under reduced pressure to give a yellow solid. The combined residues were triturated with DCM (500 ml) then water (100 ml) and the solid collected by filtration and dried on the sinter, then under high vacuum overnight to give the title compound as a white solid (108.5 g);
Reaction SMILES: C(#N)C.[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1.[C:10]([O:18]OC(C)(C)C)(=[O:17])[C:11]1C=CC=CC=1>[Cu].C(O)(=O)C>[C:10]([O:18][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]1)(=[O:17])[CH3:11]
Reactant: C1=CCCCC1
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Cu]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)OC1C=CCCC1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A mixture of 1.100 g of the copper complex of N-salicylidene-3-amino-3-deoxy-1,2-O-isopropylidene-5-O-triphenylmethyl-α-D-ribofuranose, 0.70 g of copper powder, 15 ml of acetonitrile, 5 ml of acetic acid, 15 ml of cyclohexene and 5 of t-butyl peroxybenzoate was stirred at room temperature for 9 hours in a nitrogen atmosphere. After filtering the reaction solution, the filtrate was treated in the same manner as in Example 1 to obtain 1.80 g of 2-cyclohexenyl acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>C(O)C.C(O)(C)C>[N:8]1([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: C1CNCCN1
Reactant: Clc1ncccn1
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: CC(C)O
Solvent: CCO
Product: c1cnc(N2CCNCC2)nc1

Procedure:
A mixture of 3.2 g of 2-chloropyrimidine and 12.1 g of anhydrous piperazine in 100 ml of absolute ethanol is heated at reflux for 18 hours, then it is thoroughly evaporated under reduced pressure and in the warm. The residue is taken up with 400 ml of diethyl ether, the solution thus obtained is washed with 10 ml of an aqueous solution of sodium hydroxide 1:1, then with 20 ml of water. The organic solution is dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The oil thus obtained is dissolved in 30 ml of isopropanol and 4.38 g of 2-naphtalenesulfonic acid dissolved in 30 ml of isopropanol are added to the solution at about 60° C. From the solution thus obtained a product crystallizes which is filtered and dried to give 2-(1-piperazinyl)pyrimidine napsilate identical to the product of Example 1.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.C(N(CC)CC)C.Cl.Cl.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][C@@H:23]([CH3:27])[CH2:22]1.CO>C1COCC1>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][C@@H:23]2[CH3:27])[N:3]=[C:4]([CH3:10])[N:5]=1
Reactant: C[C@H]1CN(C)CCN1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@@H]2C)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.6 %

Procedure:
To 4,6-dichloro-5-fluoro-2-methylpyrimidine (0.309 g, 1.71 mmol) and triethylamine (0.83 mL, 5.98 mmol) in THF (6.0 mL) was added (3S)-1,3-dimethylpiperazine dihydrochloride (Example 64) (0.320 g, 1.71 mmol). MeOH (3 mL) was added to improve solubility and the reaction was stirred for 4 days at room temperature. The solvent was removed in vacuo, and ether, THF and water were added to the resulting residue. The organics were dried (Na2SO4) and concentrated in vacuo to provide 4-chloro-6-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine as an orange solid (0.277 g, 63%). LCMS: (M+H)+=259.3.