Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C([Li])CCC.[CH3:15][N:16]([CH3:30])[C:17]1[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:18]=1C(Cl)=O.C(O[Li])(=O)CC(O[Li])=O.Cl>C1COCC1.O>[CH3:15][N:16]([CH3:30])[C:17]1[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:18]=1[C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: CN(C)c1c(F)c(F)c(F)c(F)c1C(=O)Cl
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: [Li]CCCC
Agent: [Li]OC(=O)CC(=O)O[Li]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1N(C)C
Reaction time: 1.75 h

Procedure:
To a solution of 4.76 g (36 mmol) of malonic acid monoethyl ester and 75 ml of THF at -35° was added 25 ml (40 mmol) of 1.5N n-butyl lithium solution. The remaining 25 ml (40 mmol) of 1.5N butyllithium solution was added at 0°. After cooling to -78°, a solution of the 4.8 g of 2-(dimethylamino)-3,4,5,6-tetrafluorobenzoyl chloride in 50 ml of THF was added to the dilithio malonate over a 15 minute period. The reaction mixture was stirred for 1.75 hours while the temperature came up to -30°. The reaction mixture was poured into ice, water, and 50 ml of 1N HCl. The mixture was extracted with ether and the ether extract was washed with H2O, 5% NaHCO3, and HCl. After drying over MgSO4 the ether solution was concentrated to 4.4 g of oily product. NMR spectra indicated the desired product.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:19]([N:22]=[C:23]=[O:24])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:23](=[O:24])[NH:22][CH2:19][CH2:20][CH3:21])=[CH:9][CH:8]=2)=[CH:17][CH:18]=1
Reactant: CCC(O)(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: CCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CCCNC(=O)Oc1ccc(C(O)(CC)c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
12.3 g. of 4-fluoro-4'-hydroxy-α-ethyl-benzhydrol, 4.68 g. of n-propyl-isocyanate and 0.7 g. of anhydrous, powdered potassium carbonate in 61 ml. of acetonitrile containing 15 μlit. of a 50% aqueous ethanol solution are refluxed under stirring. When the reaction is complete, the reaction mixture is cooled to room temperature, potassium carbonate is filtered off and acetonitrile is distilled off under reduced pressure. The residue is dissolved in benzene, the benzene solution is shaken with a 5% aqueous sodium hydroxide solution and washed to neutral with water. The organic phase is dried over anhydrous magnesium sulfate, filtered, and benzene is distilled off under reduced pressure. Crystallization of the residue from a mixture of ethyl acetate and n-hexane yields 13.6 g. of the desired compound, melting at 107° to 108° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[OH-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccccn3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NC(=O)c2ccccn2)c1
Yield: 37.6 %

Procedure:
A mixture of methyl 2-(4-fluoro-3-(picolinamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (84 mg, 0.19 mmol) and sodium hydroxide (62 mg, 1.55 mmol) in tetrahydrofuran (10 mL), water (2 mL) was heated to reflux for 20 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residue was acidified by 1 M hydrochloric acid solution to pH=5-6. The precipitated white solid was collected by filtration and dissolved in acetone, dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave crude product, which was purified by recrystallization from dichloromethane/Hexane/tetrahydrofuran to afford 30 mg of 2-(4-fluoro-3-(picolinamido)-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 42.1%. MS (ES+APCI) M+1=420.1.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[N:14][C:13]([N:16]2[CH:20]=[C:19]([CH3:21])[N:18]=[N:17]2)=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.Cl[C:23]([C:25]([O:27][CH3:28])=[O:26])=[O:24]>C(Cl)Cl.C[N+]([O-])=O>[CH3:28][O:27][C:25](=[O:26])[C:23]([C:9]1[C:8]2[C:12](=[C:13]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[N:17]3)[N:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][CH:10]=1)=[O:24]
Reactant: COc1cnc(-n2cc(C)nn2)c2[nH]ccc12
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: COC(=O)C(=O)c1c[nH]c2c(-n3cc(C)nn3)ncc(OC)c12
Temperature: 0 °C
Reaction time: 18 h
Yield: 17.3 %

Procedure:
To a solution of AlCl3 (1.382 g, 10.36 mmol) in CH2Cl2 (4 mL) and MeNO2 (1 mL) was added 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindole (0.155 g, 0.677 mmol) as a solid. After dissolution of the starting material (ca. 5 min), ClCOCO2Me (0.29 mL, 3.15 mmol) was added and the mixture was allowed to stir for 18 h. Another portion of ClCOCO2Me (0.29 mL, 3.15 mmol) was then added and stirring continued for a further 24 h. The mixture was subsequently cooled to 0° C., quenched by the slow addition of 1 M aqueous NH4OAc and then extracted with EtOAc. The aqueous layer was separated and acidified with 6 M HCl and then the resultant precipitate was filtered and dried to give the title acid (0.158 g, 69%): LCMS: m/e 302 (M+H)+. The organic layer was washed (H2O, brine), dried (Na2SO4) and evaporated to give 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid methyl ester (0.037 g, 15%): LCMS: m/e 316 (M+H)+. This material was hydrolyzed by dissolving in MeOH (2 mL) and treating with 1M NaOH (0.3 mL). The mixture was allowed to stir for 4 h, at which point the solvent was removed and the residue diluted with H2O (4 mL). The mixture was then acidified to pH 1 using 6N HCl and the precipitated acid was filtered and dried to give a further 0.021 g of the title compound. Total yield=0.179 g (78%). Preparation of 4-(1-Phenyl-1-(3-hydroxy-1-butyl-1-yl)-methylene)-piperidine-1-carboxylic acid tert-butyl ester:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[O:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29](O)=[O:30]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:29]([CH:25]3[CH2:26][CH2:27][CH2:28][O:24]3)=[O:30])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(O)C1CCCO1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C3CCCO3)C2)cc1

Procedure:
68 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 26 mg (0.22 mmol, 1.1 eq.) of tetrahydrofuran-2-carboxylic acid were reacted according to General Method 1. Yield: 67 mg (81% of theory)
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1cc2ccccc2s1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 1-Benzothiophene-2-sulfonyl chloride (23 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.9 mg). MS m/z 385 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].[CH3:21][CH:22]([CH2:24][CH2:25][CH2:26][C@H:27]([C@@H:29]1[C@:46]2([CH3:47])[C@H:32]([C@H:33]3[C@H:43]([CH2:44][CH2:45]2)[C@:41]2([CH3:42])[C:36]([CH2:37][C@@H:38]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]I)[CH2:39][CH2:40]2)=[CH:35][CH2:34]3)[CH2:31][CH2:30]1)[CH3:28])[CH3:23].C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][O:48][C@H:38]1[CH2:39][CH2:40][C@@:41]2([CH3:42])[C:36](=[CH:35][CH2:34][C@@H:33]3[C@@H:43]2[CH2:44][CH2:45][C@@:46]2([CH3:47])[C@H:32]3[CH2:31][CH2:30][C@@H:29]2[C@H:27]([CH3:28])[CH2:26][CH2:25][CH2:24][CH:22]([CH3:23])[CH3:21])[CH2:37]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@H]1OC(C)=O
Yield: 61 %

Procedure:
2,3,4-Tri-O-acetyl-1-thio-β-L-fucopyranose (10 mmol) is treated with 6-(5-cholesten-3β-yloxy)hexyl iodide (10 mmol) in dichloromethane (30 ml) containing triethylamine (10 mmol). The reaction takes place in 1 day at room temperature under nitrogen. The resulting solution is washed with distilled water (20 ml) and dried with anhydrous sodium sulfate. The filtered solution is concentrated to form a syrup which is put on a silica gel column and eluted with chloroform followed by 1.0% ethanol in chloroform. The fractions containing the title compound, as determined by thin layer chromatography, are pooled and evaporated to give the title compound in 61% yield [α]D -4° (c 1.5, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[OH-].[K+].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:26])([F:28])[F:27]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cc(Cl)ccc2Cl)c(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2,5-dichloroaniline (1.6 g.) in dry dimethylformamide (10 ml.) potassium hydroxide (1.0 g.) was added in small portions over 5 minutes, and stirring continued for a further 15 minutes. To the resultant solution was added 2-chloro-3,5-dinitrobenzotrifluoride (2.7 g.) in small portions over 5 minutes. When the addition was complete the mixture was stirred for 30 minutes at 20° C, after which concentrated hydrochloric acid was added to acidify the mixture. Industrial methylated spirit (10 ml.) was then added, the mixture stirred for further 15 minutes and then poured into water (150 ml.) The solid precipitate was collected by filtration, washed with water and dried to yield 2(2,5-dichloroanilino)-3,5-dinitrobenzotrifluoride, melting point 125°-126° C.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[CH:19][C:18]=2[C:22]([OH:24])=O)=[CH:13][CH:12]=1.[CH3:25][CH:26]1[NH:30][CH2:29][C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([OH:31])[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:21][N:20]=[CH:19][C:18]=2[C:22]([N:30]2[CH:26]([CH3:25])[CH2:27][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([OH:31])[CH2:29]2)=[O:24])=[CH:15][CH:16]=1
Reactant: CC1CC(O)(c2ccccc2)CN1
Reactant: O=C(O)c1cnoc1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CC(O)(c2ccccc2)CN1C(=O)c1cnoc1-c1ccc(F)cc1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.04 mmol) was added to a solution of 5-(4-fluorophenyl)isoxazole-4-carboxylic acid (8 mg, 0.04 mmol), 5-methyl-3-phenylpyrrolidin-3-ol (7 mg, 0.04 mmol) and TBTU (15 mg, 0.048 mmol, 1.2 equ.) in DMF (0.3 mL) at rt. The reaction mixture was left at rt for 2 h. The crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (11 mg). MS (ESI, pos. ion) m/z: calcd for C21H19FN2O3: 366.1380, found 366.1391.
Reaction SMILES: Br[CH2:2][C:3]([CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][CH2:41][NH2:42]>C(#N)C>[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][CH2:41][NH:42][CH2:2]/[C:3](/[CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C=C(CBr)COc2cccc3ccccc23)cc1
Reactant: CN1CCCC1CCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(/C=C(/CNCCC2CCCN2C)COc2cccc3ccccc23)cc1
Yield: 48 %

Procedure:
Methyl 4-[2-bromomethyl-3-(naphthalen-1-yloxy)-propenyl]-benzoate (412 mg, 1 mmol) was dissolved acetonitrile (5 ml) in a 100 ml vessel at 0° C., and thereto triethylamine (0.21 ml, 1.5 mmol, 1.5 eq.) and 2-(1-methylpyrrolidin-2-yl)ethylamine (R1′″NH2; 0.22 ml, 1.5 mmol, 1.5 eq.) were added while stirring. The resulting mixture was heated from 0° C. to room temperature, and then reacted for 4 hours. After the completion of reaction, the solvent was distilled off, and the residue thus obtained was extracted with ethyl ester. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 220 mg of the title compound as pale yellow oil (yield 48%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:11][O:9][C:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: Cc1cccnc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ncccc1C
Yield: 57.1 %

Procedure:
Heat a mixture of 3-methylpicolinic acid (1.0 g, 7.3 mmol), potassium carbonate (4.1 g, 29.7 mmol), and iodomethane (4.4 g, 31.0 mmol) in acetone (35 mL) overnight under reflux. Filter, wash the residue with EtOAc, and concentrate in vacuo. Pass through a short plug of silica gel eluting with hexane/EtOAc (1:1) to provide 2-methoxycarbonyl-3-methylpyridine as a pale yellow liquid (630 mg, 57%). To a solution of 2-methoxycarbonyl-3-methylpyridine in anhydrous THF (10 mL) at 0° C., add with stirring a solution of 1M lithium aluminum hydride in THF (5 mL, 5 mmol), and continue stirring for 30 min at 0° C. Allow the mixture to warm to ambient temperature and quench cautiously with 0.5M aqueous NaOH. Heat the mixture at 60° C. for 40 min, cool to ambient temperature, extract with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:3) to give the desired intermediate (90 mg, 18%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: Cn1cccc1CCN
Product: Cn1cccc1CCNS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrole and 2,4,5-trichlorobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][CH3:17])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[N:22]=[CH:21][N:20]=1>CN(C=O)C>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:1][C:4]2[CH:5]=[C:6]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][CH3:17])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:24]=1
Reactant: COc1ccccc1-c1cc(Cl)ncn1
Reactant: CCCNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: CCCNS(=O)(=O)Cc1cccc(Nc2cc(-c3ccccc3OC)ncn2)c1
Temperature: 80 °C

Procedure:
A mixture of (3-nitrophenyl)-N-propylmethanesulfonamide (0.114 g, 0.5 mmol) and 4-chloro-6-(2-methoxyphenyl)-pyrimidine (0.110 g, 0.5 mmol) in DMFA (3 mL) was stirred at 80° C. till the end of the reaction (TLC control) and then concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica to afford the (3-[6-(2-methoxyphenyl)-4-pyrimidinyl]aminophenyl)-N-propylmethanesulfonamide.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([CH2:20][OH:21])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH2:10][CH2:9]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:21][CH2:20][C:6]([F:5])=[CH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Yield: 93 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (1.4 ml), 1-(2-fluoro-3-hydroxyprop-1-enyl)-1-(3,4-methylenedioxyphenyl)cyclopropane (Example 14) (0.68 g), benzene (40 ml) and pyridine (0.26 ml) to yield the title compound (0.73 g, 93%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13]C(O)=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C([N:23](CC)C(C)C)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13][N:23]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(CC(=O)O)CC(=O)c1ccc2c(c1)OCO2
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(C)CN=C(c2ccc3c(c2)OCO3)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.2 %

Procedure:
To a solution of 5-(1,3-benzodioxol-5-yl)-3,3-dimethyl-5-oxopentanoic acid (444 mg, 1.68 mmol) and N,N-diisopropylethylamine (0.292 mL, 1.68 mmol) in chloroform, add diphenylphosphorylazide (0.364 mL, 1.68 mmol). Stir at room temperature for 2 days, then treat with 2N NaOH. After 1 h, dilute the reaction with chloroform and water, then separate the organic layer and dry with magnesium sulfate, filter, and concentrate under reduced pressure to obtain 132 mg (36%) of the title compound. MS: 218 [M+H]+; 1H NMR (300 MHz, CDCl3): δ 7.40 (s, 1H), 7.20-7.24 (m, 1H), 6.78-6.81 (m, 1H), 6.00 (s, 2H), 3.75-3.74 (m, 2H), 2.72-2.71 (m, 2H) and 1.16 (s, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.C1(C)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.O[CH2:43][CH2:44][O:45][CH2:46][C:47](=[O:63])[O:48][CH2:49][CH2:50][O:51][CH2:52][C:53](=[O:62])[O:54][CH2:55][CH2:56][O:57][CH2:58][C:59]([OH:61])=[O:60]>C1(C)C=CC=CC=1>[O:60]1[CH2:43][CH2:44][O:45][CH2:46][C:47](=[O:63])[O:48][CH2:49][CH2:50][O:51][CH2:52][C:53](=[O:62])[O:54][CH2:55][CH2:56][O:57][CH2:58][C:59]1=[O:61]
Reactant: O=C(O)COCCOC(=O)COCCOC(=O)COCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1COCCOC(=O)COCCOC(=O)COCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
To a stirred solution of triphenylphosphine (4.68 g, 17.85 mmol) in a dichloromethane/toluene 1/1 mixture (1.5 l) was added at room temperature DEAD (8.2 ml, 44.63 mmol). Reaction mixture stirred at room temperature for 10 min then a toluene solution of hydroxyacid 12 (1.18 g, 3.57 mmol) was added. Mixture was stirred at room temperature and concentrated. Careful flash chromatography on silica gel (EtOAc/pentane 1/1 then 2/1 then EtOAc 100%) afforded cyclic 14 as a white solid (670 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[CH2:23](O)C>S(=O)(=O)(O)O.C(OCC)(=O)C>[CH2:1]([O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1)[CH3:23]
Reactant: CCO
Reactant: COC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 20 %

Procedure:
A solution of [5-(4-fluorophenylcarbamoyl)pyridin-2-yloxy]acetic acid methyl ester (0.030 g, 0.99 mmole), ethanol (2 mL), and sulfuric acid (1 drop) was heated in a sealed tube at 80° C. After 6 h the reaction mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate and dried over sodium sulfate. Removal of the solvents provided 6 mg (20%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s 1H), 8.66 (m, 1H), 8.22 (m, 1H), 7.73 (m, 2H), 7.16 (m, 2H), 7.04 (m, 1H), 4.96 (s, 2H); 4.11 (m, 2H); 1.16 (m, 3H); MS (EI) m/z 317.17 (M−H)−.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([CH2:19][OH:20])[NH:13][CH2:14]2.N1C=CN=C1.[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27].BrC1C=CC=C2C=1C[C@H](CO)N(C(OC(C)(C)C)=O)C2>ClCCl.CN(C)C1C=CN=CC=1>[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][C@H:12]([CH2:19][O:20][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[NH:13][CH2:14]2
Reactant: OC[C@H]1Cc2c(Br)cccc2CN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)(C)OC(=O)N1Cc2cccc(Br)c2C[C@@H]1CO
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add trifluoroacetic acid (75.5 mL, 998.3 mmol) to solution of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (15.5 g, 45.3 mmol) in dichloromethane (226 mL) at room temperature. Stir 30 min and concentrate under reduced pressure. Dry under vacuum to give [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid as a wet solid. Dissolve [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid in dichloromethane (753 mL). Add 1H-imidazole (51.3 g, 753 mmol), N,N-Dimethyl-4-pyridinamine (460 mg, 3.77 mmol), and t-butyldimethylchlorosilane (13.6 g, 90.4 mmol). Stir at room temperature overnight. Add saturated ammonium chloride solution and extract with dichloromethane. Dry the dichloromethane extracts over sodium sulfate, filter, and concentrate under reduced pressure. Combine with the crude product from a substantially same reaction run with 19.4 mmol of tert-butyl (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-40% gradient) to give the title compound (14.3 g, 40.1 mmol). MS (m/z): 356 (M+1).