Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[N:31][CH:32]=1>>[F:33][C:30]1[N:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1
Reactant: Fc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Fc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-2-fluoropyridine (237 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (470 mg, 69%). MS (ISP) 451.1 [(M+H)+]; mp 213-216° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[C:4](Cl)[N:3]=1>C1COCC1.CCN(CC)CC.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)cc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nccc(Oc2ccc3c(C(=O)O)cccc3c2)n1

Procedure:
24.4 g (77.5 mMol) 6-(2-amino-6-chloro-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid in 3.5 l THF and 100 ml Et3N are hydrogenated in the presence of 15 g Pd/C (10%; Engelhard 4505). The catalyst is filtered off and washed extensively with THF. Partial concentration of the filtrate precipitates the title compound: MS: [M+1]+=282.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:10]2[CH2:15][O:14][CH2:13][C@@H:12]3[CH:16]=[CH:17][CH2:18][C:19](=[O:20])[N:11]23)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([C@@H:10]2[CH2:15][O:14][CH2:13][C@@H:12]3[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[N:11]23)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=C1CC=C[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N12
Yield: 100.1 %

Procedure:
Platinum oxide (20.1 mg) was added to a solution of (4R,9aS)-4-(3,4,5-trifluorophenyl)-3,4,7,9a-tetrahydro-1H-pyrido[2,1-c][1,4]oxazin-6-one (250 mg) in methanol (6 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for two hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 252 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: C(O[C:4](=[O:35])[C:5]([O:10][CH2:11][C:12]([C:27]1[C:32]([F:33])=[CH:31][N:30]=[C:29]([Br:34])[CH:28]=1)([NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH3:13])([CH2:8][F:9])[CH2:6][F:7])C.[NH3:36].N.CO>CO>[Br:34][C:29]1[CH:28]=[C:27]([C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:16])=[O:17])([CH3:13])[CH2:11][O:10][C:5]([CH2:6][F:7])([CH2:8][F:9])[C:4]([NH2:36])=[O:35])[C:32]([F:33])=[CH:31][N:30]=1
Reactant: CCOC(=O)C(CF)(CF)OCC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F
Reactant: N
Solvent: CO
Product: CC(COC(CF)(CF)C(N)=O)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F
Reaction time: 16 h

Procedure:
A solution of 2-[2-(2-bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3-fluoro-2-fluoromethyl-propionic acid ethyl ester (970 mg, 1.660 mmol) and 7M NH3 in MeOH (10 ml) was stirred in a in a sealed glass vial at 55° C. for 20 h. Another 3 ml of 7N NH3/MeOH were added and stirring was continued for 16 h at 55° C. The reaction mixture was concentrated and yielded the title compound as a yellow solid that was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH:20][C:31](=[O:33])[CH3:32])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(N)c3)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(-c2nccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 60.4 %

Procedure:
To a stirred and cooled solution of 3-{4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidin-2-yl}-phenylamine (example 326) (0.150 g, 0.369 mmol) in EtOAc (2 mL) and sat. NaHCO3-sol. (1 mL) was added acetyl chloride (0.030 mL, 0.406 mmol) and the mixture was stirred at 23° C. for 1 h. Diluted with EtOAc, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by trituration with diethyl ether to give the title compound as a white solid (0.100 g, 60%). MS (ISP) 449.3 [(M+H)+].
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5([C:31]#[N:32])[CH2:30][CH2:29]5)[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)=[N:9][N:8]2[CH:34]=1)(=O)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5([C:31]#[N:32])[CH2:30][CH2:29]5)[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)=[N:9][N:8]2[CH:34]=1
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.7 %

Procedure:
A mixture of N-{3-[(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (2.20 g, 4.86 mmol), 4N hydrochloric acid-ethyl acetate solution (35 mL) and methanol (35 mL) was stirred at room temperature for 14 hr. The reaction mixture was neutralized by the addition of 8N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (1.63 g, 82%) as a yellow powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[C:5]([CH2:21][OH:22])[N:4]=1.I[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33].C(N(C(C)C)CC)(C)C>C(#N)C>[OH:22][CH2:21][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]=[C:3]([CH2:2][OH:1])[N:4]=1
Reactant: COCCOCCOCCI
Reactant: CCOC(=O)CCCNCCOc1cc(CO)nc(CO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCCN(CCOCCOCCOC)CCOc1cc(CO)nc(CO)c1
Temperature: 80 °C
Yield: 19.3 %

Procedure:
To a solution of 180 mg of ethyl 4-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethylamino]-butanoate in 18 ml of acetonitrile was added 207 mg of 1-iodo-2-[2-(2-methoxy-ethoxy)-ethoxy]-ethane and 192 μl of diisopropylethylamine. The mixture was heated for 3 days at 80° C. and then concentrated under reduced pressure and purified by flash chromatography on silica (Merck SuperVarioFlash 15 g column, Si60 15-40 μm), using a DCM/MeOH/water mixture (40/5/0.5). The fractions containing the desired product were combined and concentrated under reduced pressure. 51 mg of ethyl 4-([2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-amino)-butanoate were obtained. LC/MS (B): tr=0.70 min; [M+H]+: m/z 459.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([NH:18][C:19]1[C:20](=[O:38])[N:21]([C:25]2[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=2[Cl:37])[C:28]([NH:30][CH:31]2[CH2:33][CH2:32]2)=[O:29])[CH:22]=[CH:23][N:24]=1)([CH3:17])[CH3:16])C1C=CC=CC=1.B(Br)(Br)Br.[CH2:43](Cl)Cl>O>[CH:31]([NH:30][C:28](=[O:29])[C:27]1[CH:34]=[CH:35][C:36]([Cl:37])=[C:25]([N:21]2[CH:22]=[CH:23][N:24]=[C:19]([NH:18][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[OH:8])([CH3:17])[CH3:16])[C:20]2=[O:38])[CH:26]=1)([CH2:33][CH3:32])[CH3:43]
Reactant: CC(C)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2Cl)c1=O)c1ccccc1OCc1ccccc1
Reactant: ClCCl
Agent: BrB(Br)Br
Solvent: O
Product: CCC(C)NC(=O)c1ccc(Cl)c(-n2ccnc(NC(C)(C)c3ccccc3O)c2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-[3-({1-[2-(benzyloxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-4-chloro-N-cyclopropylbenzamide (Example 330g, 2.23 g) dissolved in DCM (30 mL) was treated with boron tribromide (8.43 mL of a 1M solution in DCM) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with water (200 mL), and extracted with dichloromethane (250 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was triturated with diethyl ether (50 mL) to afford the subtitle compound (1.760 g).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([O:12]CC)=O)[CH2:3][CH2:4][C:5](OCC)=[O:6].[OH-].[NH4+:16]>>[NH:1]1[CH:2]([C:10]([NH2:16])=[O:12])[CH2:3][CH2:4][C:5]1=[O:6]
Reactant: [NH4+]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: [OH-]
Product: NC(=O)C1CCC(=O)N1
Reaction time: 10 h
Yield: 78.6 %

Procedure:
A mixture of 575 g diethyl glutamate and 700 ml concentrated ammonium hydroxide was stirred for 10 hours, and kept in the freezer at (-20° C.) for 5 hours. The resulting white crystalline solid was filtered, washed with 500 ml ethanol followed by 200 ml ether and dried in a vacuum oven at 70° C. for 16 hours to remove the water of crystallization giving 270 g (78.6%) of white crystalline 2-pyrrolidone-5-carboxamide.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[N:7][NH:6][C:5]2=S)[CH2:3][CH2:2]1>[Ni].CCO>[CH:1]1([N:4]2[CH:5]=[N:6][N:7]=[C:8]2[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: S=c1[nH]nc(-c2ccncc2)n1C1CC1
Agent: [Ni]
Solvent: CCO
Product: c1cc(-c2nncn2C2CC2)ccn1
Temperature: 60 °C
Yield: 72.1 %

Procedure:
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione (11.11 g, 51 mmol) was slowly added to wet Raney nickel (90 g ) in EtOH (200 mL) in portions. The reaction mixture was heated at 60° C. for 3.5 h and then filtered through celite. The filtrate was concentrated to give the title compound (6.85 g, 72.3%). 1H-NMR: 8.76 (d, 2H), 8.71 (s, 1H), 7.95 (d, 2H), 3.75(m, 1H), 1.08 (m, 2H) and 0.94 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([O:36][C:37]([N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28]([C:40]4[N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH:43]=[CH:42][CH:41]=4)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(I)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(-c3cccn3C(=O)OC(C)(C)C)cc2)CC1
Yield: 56 %

Procedure:
4-[3-Formyl-1-(4-iodophenyl)-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester is reacted with 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid as described in Example 66 to afford 4-{1-[4-(tert-butoxylcarbonyl-1H-pyrrol-2-yl)-phenyl]-3-formyl-1H-indol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester as a beige solid (56% yield). ESI/MS 571 (M+1), 515 [M−C(CH3)3]; NMR (CDCl3) 10.28 (1H, s); 8.27 (1H, d, J=6 Hz); 7.59 (2H, d); 7.41 (6H, m); 6.32 (2H, m); 3.36 (8H, m); 1.46 (9H, s); 1.44 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]2[C:14]3[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=3)[O:8][C:7](=[O:16])[C:6]=2[CH:17]=1.II>CC(C)=O>[F:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]1[C:6](=[C:17]3[C:2](=[CH:3][C:4]=1[CH3:18])[NH:1][C:4]([CH3:18])([CH3:5])[CH:3]=[C:2]3[CH3:17])[C:7](=[O:16])[O:8]2
Reactant: Cc1cc(N)cc2c(=O)oc3cc(F)ccc3c12
Agent: II
Solvent: CC(C)=O
Product: CC1=CC(C)(C)Nc2cc(C)c3c(c21)c(=O)oc1cc(F)ccc13
Temperature: 110 °C
Reaction time: 96 h
Yield: 78 %

Procedure:
In a pressure tube, 8-amino-3-fluoro-10-methylbenzo[c]chromen-6-one (Reference Compound No. 1-4-(6), 6.13 g, 25.2 mmol) was dissolved in acetone (175 mL) and iodine (2.56 g, 10.1 mmol) was added thereto, then the pressure tube was sealed, and then the reaction mixture was stirred at 110° C. for 4 days. After cooling down, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (6.35 g) as a brown solid. (Yield 78%)
Reaction SMILES: C[O-].[Na+].[BH4-].[Na+].[SH:6][CH2:7][CH2:8][CH2:9][OH:10].CS(O[CH2:16][CH:17]([O:40][CH3:41])[CH2:18][O:19][CH2:20][CH2:21][CH:22]([CH3:39])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])(=O)=O>O1CCCC1.CO>[OH:10][CH2:9][CH2:8][CH2:7][S:6][CH2:16][CH:17]([O:40][CH3:41])[CH2:18][O:19][CH2:20][CH2:21][CH:22]([CH3:39])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36]
Reactant: COC(COCCC(C)CCCC(C)CCCC(C)CCCC(C)C)COS(C)(=O)=O
Reactant: OCCCS
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(COCCC(C)CCCC(C)CCCC(C)CCCC(C)C)CSCCCO
Yield: 96.5 %

Procedure:
To 30 ml of teterahydrofuran are added 11.8 ml of a methanol solution of sodium methoxide (28% solution), 0.57 g of sodium borohydride and 4.14 g of 3-mercaptopropanol, to which is added dropwise a solution of 6.97 g of 2-methoxy-3(3,7,11,15-tetramethylhexadecyloxy)propyl methanesulfonate in 50 ml of tetrahydrofuran at room temperature with stirring under nitrogen streams. Thereafter, the reaction mixture is stirred at room temperature for 16 hours. The solvent is distilled off under reduced pressure and the residue is extracted with hexane. The extract layer is washed successively with water, dilute hydrochloric acid, water, an aqueous sodium bicarbonate solution and then with water. After drying, the solvent is distilled off under reduced pressure to leave 6.67 g of the captioned compound as an oily substance.
Reaction SMILES: [NH2:1][C:2](=[O:29])[CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23](OCC)=[O:24])[C:5]1=[O:28].[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[NH2:1][C:2](=[O:29])[CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:24])[C:5]1=[O:28]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(N)=O)c1=O
Product: NC(=O)Cn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-(2-amino-2-oxoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(2-aminoethyl)morpholine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white rigid foam: 1H NMR (CDCl3) δ 10.36 (1H, m), 8.56 (1H, s), 7.61 (1H, s), 7.15 (2H, dd, J=8.5, 5.5 Hz), 7.01 (2H, t, J=8.5 Hz), 6.87 (1H, br s), 5.65 (1H, br s), 4.81 (2H, s), 4.12 (2H, s), 3.98 (4H, m), 3.91 (2H, q, J=6 Hz), 3.75 (2H, m), 3.37 (2H, t, J=6 Hz), 2.92 (2H, br); HRMS calcd for C24H26FN5O5+H+: 484.1996. Found: 484.1987.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[CH:24][C:7]=1[O:8][CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:10][CH2:11][C:12]([O:14]CC)=[O:13].C(=O)([O-])[O-].[K+].[K+]>CO>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[CH:24][C:7]=1[O:8][CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1-c1ncco1)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1-c1ncco1
Yield: 53.1 %

Procedure:
A solution of ethyl (RS)-4-[2-(oxazol-2-yl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (140 mg) in methanol (25 mL) containing 10% w/v potassium carbonate (2 mL) is stirred at reflux for 2 hours. The reaction mixture is partitioned between 1 N HCl (50 mL) and ethyl acetate (50 mL) then the organic phase is washed with water (2×50 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure. Recrystallisation from cyclohexane/ethyl acetate gives (RS)-4-[2-(oxazol-2-yl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid as a white solid (70 mg), m.p. 112-114° C. [Elemental analysis:- C,66.8, H, 5.16, N, 3.12%. Calculated:- C,66.5, H, 5.04, N, 3.01%]
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:7]=1.[CH3:20]O>>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:20])=[O:11])=[C:8]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:7]=1
Reactant: CO
Reactant: CS(=O)(=O)Nc1cc(Cl)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)cc1NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
Thionyl chloride (21 ml) was added to methanol at 10° C. and the solution stirred for 0.5 hours before being added to 4-chloro-2-(methylsulphonylamino)benzoic acid (11.1 g). The mixture was heated under reflux conditions for 2 days after which time a further addition of thionyl chloride (6 ml) was made and reflux resumed for a further 2 days. The solvent was evaporated to dryness, water added and the mixture extracted with ethyl acetate. The extract was washed with sodium hydroxide solution (2N) then with water, dried (magnesium sulphate) and evaporated to dryness to give methyl 4-chloro-2-(methylsulphonylamino)benzoate (3.85 g) as a cream solid, NMR (CDCl3) 3.25(s,3H), 3.9(s,3H), 7.3(dd,1H), 7.6(m,1H), 7.95(d,1H), 10.2(brs,1H).
Reaction SMILES: [BH4-].[Na+].Cl.[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[O:23])[CH2:15][CH2:14]2)=[N:5]1.Cl>C(O)C>[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH:22]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[OH:23])[CH2:15][CH2:14]2)=[N:5]1
Reactant: O=C(CCCN1CCN(c2nsc3ccccc23)CC1)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCCN1CCN(c2nsc3ccccc23)CC1)c1ccc(F)cc1
Reaction time: 20 h
Yield: 69 %

Procedure:
Sodium borohydride (1.0 g., 0.026 mole) is added portionwise to a stirred suspension of 4-[4-(1,2-benzisothiazol-3-yl)-1-piperzinyl]-1-(4-fluorophenyl)-1-butanone hydrochloride (3.34 g., 0.008 mole) in 150 ml. of absolute ethanol. The mixture is stirred for a 20 hr. period, acidified with ethanolic hydrogen chloride, stirred for an additional 2 hr. period and concentrated in vacuo. Residual material is partitioned between chloroform and 1 N aqueous sodium hydroxide and the chloroform phase dried over magnesium sulfate and concentrated in vacuo to afford 2.31 g. (69% yield) of the title compound as the free base. The free base is converted to the hydrochloride in ethanol with ethanolic hydrogen chloride to afford α-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propyl]-4-fluorobenzenemethanol hydrochloride, m.p. 200°-202° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:27][O:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([NH:36]C(=O)C)=[C:31]([Cl:40])[CH:30]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])=[CH:9][CH:8]=1>CO.Cl>[OH:1][C@H:2]([CH2:27][O:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([NH2:36])=[C:31]([Cl:40])[CH:30]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])=[CH:11][CH:12]=1
Reactant: CC(=O)Nc1c(Cl)cc(OC[C@@H](O)CNCCc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc2)cc1Cl
Agent: Cl
Solvent: CO
Product: Nc1c(Cl)cc(OC[C@@H](O)CNCCc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc2)cc1Cl
Yield: 0.1 %

Procedure:
A solution of 28 mg (0,016 mmol) of the acetamide from Example 208 in 5 mL of methanol and 0.24 mL of 2N aqueous hydrochloric acid was heated at reflux for 3 days. It was then cooled and concentrated. Purification by HPLC (ODS-3, 1:1 methanol:0.1% aqueous trifluoroacetic acid) gave 6.7 mg (13%) the title compound as its bis trifluoracetate salt: 1H NMR (400 MHz, CD3OD) δ8.31 (d, 1H, J=1.5 Hz), 7.96-7.90 (m, 3H), 7.75 (dd, 1H, J=1.9, 8.7 Hz), 7.65-7.57 (m, 2H), 7.11 (s, 4H), 6.89 (s, 2H), 4.12 (m, 1H), 3.89 (dd, 1H, J=5.0, 9.9 Hz), 3.85 (dd, 1H, J=5.3, 9.9 Hz), 3.23-3.11 (m, 4 HO, 2.90-2.86 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[O:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:4][C:3](=[O:16])[NH:2][CH2:1][C:19](=[O:20])[CH2:18][Cl:17])[C:15]=2[O:14][CH2:13][CH2:12][CH2:11]1
Reactant: CNC(=O)Oc1cccc2c1OCCCO2
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: O=C(CCl)CNC(=O)Oc1cccc2c1OCCCO2

Procedure:
11.2 G. of 3,4-dihydro-2H-1,5-benzodioxepin-6-yl methylcarbamate, 100 ml. of toluene and 11.3 g. of chloroacetyl chloride are refluxed for 48 hours and then the mixture is evaporated to dryness. The yellow oil which remains is recrystallized from ether/petroleum ether (40°-45° C.). There is obtained 3,4-dihydro-2H-1,5-benzodioxepin-6-yl(chloroacetyl)methylcarbamate, m.p. 63°-64° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[CH2:33]([N:40]1[CH:45]=[CH:44][N:43]=[C:42]([C:46](O)=[O:47])[C:41]1=[O:49])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([N:40]1[CH:45]=[CH:44][N:43]=[C:42]([C:46]([NH:1][C:2]2[CH:31]=[CH:30][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[CH:17]=[CH:18][C:19]([C:22]([N:24]6[CH2:25][CH2:26][O:27][CH2:28][CH2:29]6)=[O:23])=[CH:20][CH:21]=5)[S:15][C:8]=34)=[C:4]([F:32])[CH:3]=2)=[O:47])[C:41]1=[O:49])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)c1nccn(Cc2ccccc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1)c1nccn(Cc2ccccc2)c1=O
Yield: 45 %

Procedure:
Prepared from (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (Example 129, Step A) and 4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (2% MeOH in CH2Cl2) to afford 12 mg (45%) of the desired product. LRMS (APCI pos) m/e 662.2 (M+1). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.03 (dd, 1H), 7.96 (d, if H), 7.92 (d, 2H), 7.85 (s, if H), 7.77 (d, 1H), 7.56 (m, 3H), 7.36-7.46 (m, 7H), 6.66 (d, 1H), 5.33 (s, 2H), 3.68-3.81 (m, 8H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −128.2.