Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22]
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Reactant: O=C(CCCI)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCC(=O)c3ccccc3)CC2)C1=O
Temperature: 68 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
A mixture of tert-butyl 2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (300 mg, 0.72 mmol, 1 equiv), 4-iodo-1-phenylbutan-1-one (198.5 mg, 0.72 mmol, 1 equiv) and potassium carbonate (199 mg, 1.44 mmol, 2 equiv) in N,N-dimethylformamide was stirred at 68° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using the preparative thin layer chromatography in 8% methanol in dichloromethane to afford the title compound (268 mg, 65.5%); MS for C35H41N3O4 m/z 568.31 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>N1C=CC=CC=1.C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[Si:29]([O:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][C:4]([O:6][CH3:7])=[O:5])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(O)CC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(CC(=O)OC)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
The alcohol (11Z,14Z)-methyl 3-hydroxyicosa-11,14-dienoate (3) (1.40 g, 4.14 mmol) in pyridine:THF (2:1, 30 mL) was treated with silver nitrate (913 mg, 5.40 mmol), t-butylchlorodimethyl silane (814 mg, 5.40 mmol) and stirred (60 min) The mixture was filtered through Celite and the filter cake rinsed with pyridine. The filtrate was concentrated and the residue was taken-up in CH2Cl2, washed with HCl (5%, aq.) and brine, dried, filtered and concentrated. The crude material was subjected to chromatography to yield (11Z,14Z)-methyl 3-((tert-butyldimethylsilyl)oxy)icosa-11,14-dienoate (4) (1.70 g, 91%) as a clear colorless oil. Rf 0.8 (10% EtOAc-hexanes), FW 452.79, C27H52O3Si.
Reaction SMILES: [CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:35])[CH2:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][Br:33])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:36][N:37]([CH3:39])[CH3:38]>C(O)C>[Br-:33].[CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:35])[CH2:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N+:37]([CH3:39])([CH3:38])[CH3:36])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=C(COC(=O)CCCCCBr)COC(=O)NCCCCCCCCCCCCCCCCCC
Reactant: CN(C)C
Solvent: CCO
Product: C=C(COC(=O)CCCCC[N+](C)(C)C)COC(=O)NCCCCCCCCCCCCCCCCCC
Product: [Br-]
Temperature: 60 °C

Procedure:
1-Octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane (from Preparation 9) (0.84 g) was dissolved in 33% trimethylamine in ethanol (30 ml) and heated to 60° C. in a sealed flask for 5 hours. Excess trimethylamine and ethanol were removed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.OC1C=CNC(=O)C=1.CS(O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)(=O)=O.CS(OC1CCN(C2N=CC(CCC)=CN=2)CC1)(=O)=O>>[Cl:1][C:2]1[C:3]([O:18][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: N#Cc1ccc(-n2cc(Cl)c(O)cc2=O)cc1F
Agent: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Agent: O=c1cc(O)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)cc2Cl)CC1

Procedure:
Example 267 was prepared according to procedures described in Example 173 Step C substituting 4-(5-chloro-4-hydroxy-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (prepared according to the procedure described in Step B of Example 263) for 4-hydroxypyridin-2(1H)-one and substituting tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (prepared according to the procedure described in Step C of Example 1) for 1-(5-propylpyrimidin-2-yl)piperidin-4-yl methanesulfonate except that the crude product was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (t, J=7.53 Hz, 1H), 7.37-7.46 (m, 2H), 7.30-7.36 (m, 1H), 6.00 (s, 1H), 4.54-4.68 (m, 1H), 3.58-3.71 (m, 2H), 3.40-3.56 (m, 2H), 1.93-2.07 (m, 2H), 1.78-1.93 (m, 2H), 1.49 (s, 9H). MS (ESI) 392 (M−56+H).
Reaction SMILES: C([N:8]([CH3:40])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.Br[C:42]1[CH:43]=[N:44][CH:45]=[N:46][CH:47]=1>>[ClH:27].[ClH:27].[CH3:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([C:42]2[CH:43]=[N:44][CH:45]=[N:46][CH:47]=2)=[CH:30][C:29]=1[CH2:28][N:15]([CH:12]1[CH2:11][CH2:10][CH:9]([NH:8][CH3:40])[CH2:14][CH2:13]1)[C:16]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[Cl:27])=[O:17]
Reactant: Brc1cncnc1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3cncnc3)ccc2OC)C(=O)c2sc3ccccc3c2Cl)CC1
Product: Cl

Procedure:
The title compound is prepared from boronic acid 5 (25 mg, 43 μmol) and 5-bromopyrimidine (5.6 mg, 36 μmol) in accordance with Method L2.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH:14]=S)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH2:24]([NH2:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].[OH-].[Na+].[C:39]([O-:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([O-:44])=[O:43]>C(Cl)(Cl)Cl>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH:14]=[N:36][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=CN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: CCCCCCCCCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCN=CN1CCC(C(c2ccccc2)c2ccccc2)CC1
Product: O=C(O)/C=C/C(=O)O

Procedure:
A solution of 5.54 g (0.019 mole) of 4-(diphenylmethyl)-1-piperidinecarbothioaldehyde in 20 ml of chloroform was treated with 2.65 g (1.16 ml, 0.019 mole) of methyl iodide and refluxed for one hour. The resulting solution was treated with 3.49 g (0.019 mole) of n-dodecylamine, refluxed one and one half hours, cooled, treated with aqueous sodium hydroxide and the organic layer separated. After drying, evaporation yielded an oil which was converted to the fumarate to yield 4-(diphenylmethyl)-1-N-(n-dodecyliminomethyl)piperidine fumarate; m.p. 143°-145.5° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[N:10]1([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1ccccn1
Reactant: C1CCNC1
Agent: Cl
Solvent: CCO
Product: c1ccc(CN2CCCC2)nc1
Temperature: 90 °C
Yield: 94 %

Procedure:
With stirring and external cooling with ice, a solution of 2-(chloromethyl)pyridine hydrochloride (100 g, 0.61 mol) in 95% ethanol (600 ml) is added dropwise to pyrrolidine (500 ml, 426 g, 5.99 mol) and the resulting mixture is heated to 90° C. for 1 hour. After cooling, the mixture is suction filtered, the filter residue is thoroughly washed with ether, the filtrate is concentrated in vacuo and the residue is made strongly alkaline with 40% potassium hydroxide solution. It is extracted exhaustively with ether, the extracts obtained are freed from solvent and the remaining residue is distilled in vacuo. The desired compound (93.0 g) is obtained. Boiling point 19 mm Hg 118°-121° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
A mixture of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (745 mg, 2.3 mmol), benzoic acid (337 mg, 2.76 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.31 g, 3.45 mmol) in dichloromethane (10 mL) and triethyl-amine (0.8 mL, 5.75 mmol) was stirred at 25° C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-benzoylamino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (984 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C27H28N2O3 (M+H)+: 429.54, observed: 429.1.
Reaction SMILES: [C:1]1([C:11]2([C:14]#N)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-:16].[K+].C(O)C[OH:20]>O>[C:1]1([C:11]2([C:14]([OH:20])=[O:16])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2cccc3ccccc23)CC1
Reactant: [OH-]
Reactant: OCCO
Agent: [K+]
Solvent: O
Product: O=C(O)C1(c2cccc3ccccc23)CC1
Reaction time: 16 h

Procedure:
A mixture of 1-(1-naphthyl)cyclopropanecarbonitrile (60.7 g, prepared in a similar manner to that described in Example N9) and 10% aqueous potassium hydroxide solution was stirred and heated under reflux for 16 hours. Ethylene glycol (250 ml) was added and the mixture was heated under reflux for 5 hours. Each time complete solution was achieved, further water was added to cloud point. Water (500 ml) was added and the mixture was allowed to stand for 16 hours. The resulting solid was removed by filtration. The filtrate was diluted with water (800 ml), filtered, and the filtrate acidified by addition of dilute hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried in air, yielding 1-(1-naphthyl)cyclopropane carboxylic acid (25.9 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH:4]=[CH:5][C:6]([OH:8])=O.S(Cl)(Cl)=O.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>ClCCl.CN(C)C=O>[CH2:14]([N:16]([CH2:17][CH3:18])[C:6](=[O:8])[CH:5]=[CH:4][CH2:3][CH:2]([CH3:1])[CH3:9])[CH3:15]
Reactant: CC(C)CC=CC(=O)O
Reactant: CCNCC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C=CCC(C)C
Temperature: 28.5 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-methylhex-2-enoic acid (formula-3) (20 grams) in dichloromethane (250 ml), 2 ml of dimethyl formamide was added. To this mixture thionyl chloride (24.1 grams) was added. The reaction mixture was stirred for 2.5 hours at 28-29° C. The reaction mixture was cooled to 0-5° C. and diethyl amine was added to the reaction mixture at 5-8° C. until the pH reached to 8.5. The reaction mixture was stirred for 1.5 hours at 0-5° C. The reaction mixture was quenched with water. Separated the aqueous and organic layers. The organic layer was washed with 5% sodium bicarbonate solution and was dried over anhydrous sodium sulphate. The solvent was distilled off completely under vacuum to provide the title compound as solid.
Reaction SMILES: NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)C=1)(C)CCC(O)=O.[C:30]([C@H:34]1[CH2:39][CH2:38][C@H:37]([O:40][C:41]2[C:42]([C:61]([F:64])([F:63])[F:62])=[C:43]3[C:48](=[CH:49][CH:50]=2)[CH:47]=[C:46]([C:51]([N+:58]([O-])=O)([CH3:57])[CH2:52][CH2:53][C:54]([OH:56])=[O:55])[CH:45]=[CH:44]3)[CH2:36][CH2:35]1)([CH3:33])([CH3:32])[CH3:31]>>[NH2:58][C:51]([C:46]1[CH:45]=[CH:44][C:43]2[C:48](=[CH:49][CH:50]=[C:41]([O:40][C@H:37]3[CH2:36][CH2:35][C@H:34]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:39][CH2:38]3)[C:42]=2[C:61]([F:63])([F:64])[F:62])[CH:47]=1)([CH3:57])[CH2:52][CH2:53][C:54]([OH:56])=[O:55]
Reactant: CC(CCC(=O)O)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(N)(CCC(=O)O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Product: CC(N)(CCC(=O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1

Procedure:
4-amino-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl) pentanoic acid was synthesized as per 4-amino-4-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl) pentanoic acid (Example 207) in 26% yield using 4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-nitropentanoic acid as starting material. MS: m/z=449.71 [M-NH2]+. 1H NMR (MeOD) δ: 8.25-8.31 (m, 1H), 8.14 (d, J=9.3 Hz, 7.96 (d, J=2.3 Hz, 1H), 7.69 (dd, J=9.3, 2.5 Hz, 7.60 (d, J=9.3 Hz, 1H), 4.46-4.56 (m, 1H), 2.65-2.70 (m, 3H), 2.37-2.54 (m, 2H), 2.18-2.35 (m, 2H), 2.07-2.18 (m, 2H), 1.95 (br. s., 2H), 1.87 (s, 2H), 1.50 (br. s., 2H), 1.19-1.34 (m, 2H), 1.07-1.18 (m, 1H), 0.88-0.95 (m, 9H)
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:14])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=O)[CH3:2].[N:15]1C=CC=CC=1>CN(C=O)C>[CH3:2][C:1]1[C:4]2[CH:12]=[CH:11][C:10]3[NH:9][C:8](=[O:13])[CH2:7][C:6]=3[C:5]=2[O:14][N:15]=1
Reactant: CC(=O)c1ccc2c(c1O)CC(=O)N2
Reactant: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1noc2c3c(ccc12)NC(=O)C3
Yield: 33.9 %

Procedure:
The procedure described in Example 33d was followed with the oxime acetate obtained in step c (0.334 g, 1.35 mmol) and pyridine (0.55 mL, 6.75 mmol) in DMF (25 mL). After work-up, the residue was purified by silica gel flash chromatography (50→75% EtOAc-hexanes) to give the title compound (0.086 g, 34%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:12]=[C:11]([F:21])[CH:10]=1)C1C=CC=CC=1.[OH-].[Na+]>C1(SC)C=CC=CC=1.C(C(O)=O)(F)(F)F>[F:21][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:12]=1
Reactant: Fc1cc(OCc2ccccc2)cc(-c2ccncc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(F)cc(-c2ccncc2)c1
Temperature: 80 °C

Procedure:
A mixture of O-benzyl-3-fluoro-5-(4-pyridyl)phenol (120 mg) in thioanisole (1 mL) and CF3CO2H (0.6 mL) was heated at 80° C. for 1 h. The mixture was cooled to r.t., made basic with 10N NaOH and extracted with Et2O. The organics were washed with NaHCO3, brine, dried (MgSO4) and concentrated. The residue was triturated with hexane to provide the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=O.[OH-:21].[Na+].Cl>CO.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:11]([OH:21])=[CH:4][C:3]3[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:15][CH:16]=1
Reactant: Nc1ccccc1C=O
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1cc2ccccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
2-Aminobenzaldehyde (118 mg) and 2-bromo-1-(4-fluoro-phenyl)-ethanone (225 mg) were dissolved in methanol (5 ml) to prepare a solution. Sodium hydroxide (100 mg) and water (5 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using ethyl acetate-hexane to give 2-(4-fluorophenyl)-quinolin-3-ol (53 mg, yield 22%).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:11]([I:12])[C:4]=2[O:3]1.[BH4-].[Na+]>CO>[O:17]=[S:2]1(=[O:1])[NH:7][CH2:6][C:5]2[CH:8]=[C:9]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:10]=[C:11]([I:12])[C:4]=2[O:3]1
Reactant: CC(C)(C)c1cc(I)c2c(c1)C=NS(=O)(=O)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(I)c2c(c1)CNS(=O)(=O)O2
Temperature: 20 °C

Procedure:
To a solution of 2,2-dioxo-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine (2 g., 5.5 millimole) in methanol (75 ml.) is added sodium borohydride (0.21 g., 5.5 millimole) portionwise with stirring at 20° C. The resulting reaction solution is stirred at 20° C. for 16 hours and then concentrated in vacuo leaving a residual solid which is triturated with water (50 ml.). The insoluble solid is collected and crystallized from 40% ethanol-acetic acid (25:2, v:v) to give 2,2-dioxo-3,4-dihydro-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine as colorless crystals (1.7 g., 85%), m.p. 154°-155° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[F:42][C:43]([F:48])([F:47])[CH2:44][CH2:45]I>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:45][CH2:44][C:43]([F:48])([F:47])[F:42])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: FC(F)(F)CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(CCC(F)(F)F)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 26.4 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), 1,1,1-trifluoro-3-iodopropane (0.117 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.061 g (25%) of the title compound as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8]/[CH:9]=[CH:10]\[C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31]4[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([F:39])[CH:32]=4)=[N:25]3)[CH:18]=2)=[N:15][CH:16]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[CH2:23][N:24]2[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31]3[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([F:39])[CH:32]=3)=[N:25]2)=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC/C=C\c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC/C=C/c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
48.3 28 mg (0.051 mmol) of tert-butyl[(Z)-3-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)allyl]carbamate are dissolved in 4 ml of dichloromethane, and 79 μl (1.02 mmol) of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 15 h and evaporated. The residue is purified by means of preparative HPLC; yield: 11 mg of “A284” trifluoroacetate; HPLC: Rt=2.64 min (method C); LC-MS: 450 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][C:6](=[CH:19][N:20]([CH3:22])[CH3:21])[C:5]2=[O:16]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)N1CCC(=O)c2cc(Cl)ccc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC(=O)N1CC(=CN(C)C)C(=O)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2 g), N,N-dimethylformamide dimethyl acetal (7.009 g), and triethylamine (0.87 g) in benzene (50 ml) was refluxed with stirring for 1 hour and then about three-fourths of the solvent was distilled slowly at atmospheric pressure over a period of approximately 1 hour. To the residue was added benzene (100 ml) and the solvent was distilled again. The resulting solid was collected by filtration, washed with diethyl ether, and dried to give 6-chloro-3-dimethylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.02 g).