Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1.[H][H]>[Pt](=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(C2=CCNCC2)nc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Clc1ccc(C2CCNCC2)nc1
Reaction time: 3 h

Procedure:
Platinum dioxide (58 mg) was added to a mixture of 5-chloro-1′,2′,3′,6′-tetrahydro[2,4′]bipyridinyl (500 mg) and ethyl acetate (50 ml) under argon. The atmosphere was replaced by hydrogen and the mixture was vigorously stirred for 3 hours. The catalyst was filtered off with suction and the filtrate was concentrated. The product with the molecular weight of 196.68 (C10H13ClN2); MS (ESI): 197 (M+H+) was obtained in this way.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[C:13](=[O:16])[CH2:14][CH3:15]
Reactant: CCC(=O)Cl
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
To a mixture of m-difluorobenzene (100 ml) and anhydrous aluminium chloride (114 g) was added dropwise, while stirring, propionyl chloride (66 ml), during 45 minutes. The mixture was then stirred for 2 hours on an oil bath of 50°-55° C. The reaction mixture was cooled, to which was added methylene chloride (300 ml). The resultant solution was added by portions to ice-water (11) while stirring. Methylene chloride layer was separated, and the aqueous layer was subjected to extraction twice with methylene chloride (60 ml). Methylene chloride layers were combined and washed with water (200 ml), followed by drying over anhydrous magnesium sulfate. The solvent was distilled off to leave 2',4'-difluoropropiophenone (111.4 g) as a pale yellow oily product. 1H-NMR (CDCl3) δ: 1.17~1.24(3H), 2.92~3.05(2H), 6.82~7.02(2H), 7.89~8.03(1H)
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:19]([CH3:26])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:27].CCN=C=NCCCN(C)C.[C:42](O)(=[O:45])[CH2:43][CH3:44]>CN(C1C=CN=CC=1)C.ClCCl>[C:42]([NH:25][S:22]([C:20]1[S:21][C:17]([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:28])[C:2]([CH3:1])([CH3:29])[CH3:30])=[C:7]([CH3:27])[CH:8]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=1[CH3:26])(=[O:24])=[O:23])(=[O:45])[CH2:43][CH3:44]
Reactant: CCC(=O)O
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NS(=O)(=O)c1sc(C(CC)(CC)c2ccc(OCC(=O)C(C)(C)C)c(C)c2)cc1C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide (330 mg, 0.73 mmol), EDCI (210 mg, 1.1 mmol), propionic acid (82 μL, 1.1 mmol) and DMAP (50 mg) in dichloromethane (10 ml) is stirrred overnight. The reaction is diluted with dichloromethane and washed with 1N HCl. The organic phase is concentrated and chromatographed (Hex to 30% EtOAc/Hex) to give the title compound (92%).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([NH2:38])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[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][CH3:16].[C:39](#[N:42])[CH:40]=[CH2:41].[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:1]([O:17][CH2:18][CH:19]([NH:38][CH2:41][CH2:40][C:39]#[N:42])[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[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][CH3:16]
Reactant: C=CC#N
Reactant: CCCCCCCCCCCCCCCCOCC(N)COCCCCCCCCCCCCCCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)NCCC#N
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A mixture of 1,3-di(n-hexadecyloxy)-2-aminopropane (500 mg., 0.93 mmoles), acrylonitrile (75 ml.) and 2 wt. % aqueous sodium hydroxide solution (75 ml.) was heated to 60° C. Tetrabutyl ammonium hydroxide (1 ml. of 40 wt. % aqueous solution) was then added and the resulting mixture stirred for 15 minutes at 90° C. The reaction mixture was then cooled, causing precipitation of solids, which were isolated by filtration and found (TLC) to contain a large quantity of unreacted starting material. Using fresh acrylonitrile and aqueous sodium hydroxide solution in each cycle, the solids were treated two more times by the above procedure. The third cycle solid product was purified by silica gel chromatography (elution with toluene:ethyl acetate) [200 mg., 36% yield, m.p. 45°-46° C., ir (CHCl3) 2250 cm-1, n.m.r. (CDCl3) δ 3.07 (t, 2, --NHCH2CH2CN) and 2.53 (t, 2, --NHCH2CH2CN)].
Reaction SMILES: C(O[C:4](=[O:13])[CH:5]=[C:6](OC)[C:7]([F:10])([F:9])[F:8])C.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].[OH-].[K+].OS(O)(=O)=O>CO.O>[CH3:19][O:18][C:14]([C:15]1[S:16][C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]=1[OH:13])=[O:17]
Reactant: CCOC(=O)C=C(OC)C(F)(F)F
Reactant: COC(=O)CS
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1sc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A solution of 4,4,4-trifluoro-3-methoxy-but-2-enoic acid ethyl ester (9.6 g, 48.5 mmol) and methyl thioglycolate (4.3 mL, 48.5 mmol) in MeOH (75 mL) is cooled to 5° C. A solution of KOH (3.3 g, 58.2 mmol) in MeOH (75 mL) is then added over 30 min. The reaction mixture is stirred overnight at room temperature. The reaction mixture is then poured over a stirred mixture of ice (75 g), H2O (75 mL) and concentrated H2SO4 (4.5 mL). The mixture is extracted with EtOAc (2×250 mL). The combined extracts are washed with saturated NaHCO3. The washings are back-extracted with EtOAc. The combined organic layers are washed with brine, then dried (Na2SO4), filtered and concentrated to afford the title compound (10 g, 91%) as a brown oil which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:28][CH:29]1[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]1.[Cl:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([S:19]([N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)(=[O:21])=[O:20])[CH2:17][CH2:18]3)=[O:12])[N:8]2[C:43]2[CH:42]=[CH:41][N:40]=[C:39]([Cl:38])[CH:44]=2)=[CH:4][C:3]=1[O:28][CH:29]1[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:34]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)[nH]c3cc2Br)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1
Temperature: 35 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
A suspension of 0.15 g (0.25 mmol) [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 1), 119 mg (0.76 mmol) 2-chloropyridine-4-boronic acid, 91 mg (0.50 mmol) copper(II) acetate and 80 μL (78 mg, 1.0 mmol) pyridine in 4 ml chloroform was stirred 18 h at 35° C. The volatile components were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with a gradient of dichloromethane:methanol (100:0 to 50:50 v/v) as eluant to afford 84 mg (47%) of the title compound as a light-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:9][CH2:8][CH2:7][S:6]1)=[O:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:35]([S:38][CH2:39][CH:40]([CH3:44])[C:41](O)=[O:42])(=[O:37])[CH3:36]>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[N:9]([C:41](=[O:42])[CH:40]([CH3:44])[CH2:39][S:38][C:35](=[O:37])[CH3:36])[CH2:8][CH2:7][S:6]1)=[O:4]
Reactant: CC(=O)SCC(C)C(=O)O
Reactant: COC(=O)C1NCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)C1SCCN1C(=O)C(C)CSC(C)=O
Temperature: 0 °C

Procedure:
2-Thiazolidinecarboxylic acid methyl ester (C.A. 53, 12,281d) (4.4 l g.) and 3-hydroxybenzotriazole (4.0 g.) are dissolved in dichloromethane (40 ml.) and the solution is stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g.) in dichloromethane (5 ml.). After fifteen minutes stirring in the ice bath, and sixteen hours at room temperature, the precipitate is filtered off and the filtrate is washed neutral. The organic layer is dried and concentrated to dryness in vacuo to give 3-(3-acetylthio-2-methylpropanoyl)-2-thiazolidinecarboxylic acid methyl ester.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)(=[O:17])=[O:16])=[CH:10][CH:9]=3)[CH:5]1[CH2:4][NH:3][CH2:2]2.[CH2:29](Br)[CH:30]=[CH2:31].C(N(CC)CC)C>CN(C)C=O>[CH2:31]([N:3]1[CH2:4][C@@H:5]2[C@@H:1]([CH2:7][C@H:6]2[C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:2]1)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: O=S(=O)(Nc1ccc(C2CC3CNCC32)cc1)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
100 mg (0.43 mmol) of N-[4-(3-aza-bicyclo[3.2.0]hept-6-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide and 40 μl (0.46 mmol) of allyl bromide were dissolved in 2 ml of N,N-dimethylformamide. 0.18 ml (1.26 mmol) of triethylamine were then added to the solution. After the mixture had been stirred at room temperature for 1 hour, a further 10 μl of allyl bromide were added to the reaction mixture, which was then stirred overnight at room temperature. After the solvent had been evaporated down to dryness, the resulting residue was taken up in water and this solution was made alkaline using a 1N aqueous solution of sodium hydroxide. After that, the aqueous reaction mixture was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated down give 50 mg of title compound (yield 46%).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.[H-].[Na+].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1>O>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([O:12][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([F:6])=[CH:8][CH:9]=2)=[N:19][CH:20]=1
Reactant: OCc1ccc(F)cc1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(COc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
To an N,N-dimethylformamide (30.0 mL) solution of 4-fluorobenzyl alcohol (2.60 g, 20.6 mmol) was added sodium hydride (0.88 g, 22.2 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 10 minutes at room temperature. Next, 2,5-dibromopyridine (3.50 g, 14.8 mmol) was added at 0° C., and stirred for 19 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (3.75 g, 89.8%).
Reaction SMILES: C(OC(N[C@H]1[C@@H](N2C=CN=N2)[C@@H](C)CN(C2C=CN=CC=2NC(C2C([NH:40][C:41](=[O:50])[O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=CC3C(=CC(N4CCN(C)C(=O)C4)=CC=3)N=2)=O)C1)=O)(C)(C)C.[H][H]>CO.[Pd]>[C:41](=[O:50])([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[NH2:40]
Reactant: [H][H]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: [Pd]
Solvent: CO
Product: NC(=O)OCc1ccccc1

Procedure:
A solution of benzyl [2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(4-methyl-3-oxopiperazin-1-yl)quinolin-3-yl]carbamate (12.0 mg, 0.015 mmol) in MeOH (1.0 mL) was hydrogenated in the presence of 10% palladium on carbon (6.0 mg) under a balloon of hydrogen for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a benzyl carbamate deprotected intermediate. The intermediate was treated with 4.0 M HCl in dioxane (0.15 mL, 0.6 mmol) at room temperature for 1 h. The solution was concentrated under reduced pressure and the resulting residue was diluted with MeOH and NH4OH, filtered. The filtrate was purified by preparative LCMS (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to give the title compound as a yellow powder (5.1 mg, 60%). LCMS calc. for C28H34N11O2 (M+H)+: m/z=556.3. Found: 556.3.
Reaction SMILES: C(OC(C)C)(C)C.[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11]>CC(C)=O>[NH2:8][C@@H:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Product: CC(C)(C)[C@@H](N)C(=O)O
Yield: 90 %

Procedure:
The filtrate obtained at dibenzoyl-d-tartrate salt stage (step.ii), was treated with a small amount of diisopropyl ether to remove any traces of dibenzoyl-d-tartaric acid and was concentrated under reduced pressure at 55° C. The residue obtained was stirred with small amount of acetone and filtered to obtain D-tert-leucine as a colorless solid (90% yield, 98.8% D-tert-leucine and 1.2% L-tert-leucine).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]([O:13][C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:10][C:9]([O:13][C:14](=[O:15])[NH:16][CH:17]([C:22]([NH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:23])[CH:18]([CH3:19])[CH2:20][CH3:21])([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1cccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCc1cccnc1
Yield: 70.7 %

Procedure:
The title compound is prepared by the procedure of Example 1, using 1.0 g of 3-(aminomethyl)pyridine, 2.33 g of N-(tert-butoxycarbonyl)-L-isoleucine, 6.95 g of BOP, 11.95 g of Hunig's base and 15 ml of methylene chloride to give 2.1 g of the desired product after chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:9])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Brc1ccc([C@@H]2CO2)cc1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: O[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
(2R)-2-(4-Bromophenyl)oxirane crude (250 g) was added to morpholine (8 mL, 1 mol) in 100 mL CH2Cl2 solution at 0° C. with magnetic stirring. Montmorillonite K10 clay (20 g) was added portionwise to the brown mixture and the resulting dark brown mixture was maintained under argon for 60 h at room temperature with magnetic stirring. The clay was filtered off and the filtrate was concentrated to a brown oil. The oil was loaded onto a 3 inch plug of silica gel. 12 L of 30% EtOAc/Hexane was used to elute off less polar impurities and then 40 L of 30%-40% EtOAc/Hexane with 1% ammonia was used to elute off the desired product. The fractions were combined, concentrated, and then crystallized from Et2O. The white crystals were filtered and dried to yield the title compound (109 g, 41.6%). MS (ES) m/e 287 [M+H]+. Chiral HPLC analysis (Chiralpak AD-RH, 5 micron, 150×4.6 mm, mobile phase: 50% CH3CN/50% aqueous borate buffer (pH 9.0), 0.50 mL/min, UV 220 nm, 5 uL inj in MeOH) confirmed the product is a single enantiomer (>99% ee).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:15]([CH:16](Cl)[CH3:17])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:19])[N:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:5][C:6]1[C:15]([CH:16]([N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])[CH3:17])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:19])[N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Cl)c1cc2c(Cl)cccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(c1cc2c(Cl)cccc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 55 °C

Procedure:
Added thionyl chloride (301 μl, 4131 μmol). Obtained a clear colorless solution within minutes. Concentrated reaction mixture to dryness on the rotavap to obtain an oil, which was used without further purification. LC-MS (+esi, M+H+=260.0). Dissolved 2,5-dichloro-3-(1-chloroethyl)quinoline (215 mg, 825 μmol) in DMF (2 mL) and added phthalimide (127 mg, 866 μmol) and K2CO3 (228 mg, 1650 μmol). Submerged in oil bath and began heating to 55° C. After 10 min the temperature of the oil bath was raised to 80° C. After 30 more minutes the reaction mixture was partitioned between EtOAc:H2O. The organic layer was washed with water (3×), dried with sodium sulfate, filtered, and concentrated. The crude was solid was chromatographed on 12 g silica gel column with 0-20% EtOAc:Hex. The desired fractions were combined and concentrated to yield a white crystalline solid. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.99 (d, J=7.04 Hz, 3 H) 5.93 (q, J=7.17 Hz, 1 H) 7.64-7.70 (m, 2 H) 7.71-7.76 (m, 2 H) 7.77-7.83 (m, 2 H) 7.88-7.93 (m, 1 H) 8.95 (s, 1 H). LC-MS (+esi, M+H+=371.0)
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)#[N:20].CS(C)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Oc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])c(Oc3ccccc3)c2Cl)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 14.2 gm of 2,3-dichloro-6-nitro-1-phenoxy-benzene, 6.5 gm of 4-cyano-phenol, 40 ml of dimethylsulfoxide and 50 ml of 10 N sodium hydroxide was stirred for 3 hours at 100° C. Thereafter, the reaction mixture was diluted with water, the aqueous mixture was extracted with chloroform, the organic extract solution was dried, and the chloroform was distilled off. The residue was purified by passing it through a silicagel column and recrystallizing it from ethanol, yielding 11 gm (60.2% of theory) of the colorless crystalline title compound, m.p. 140°-142° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]([CH2:15][CH2:16][CH2:17][OH:18])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.[OH-].[Na+]>O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:18][CH2:17][CH2:16][CH2:15][C:10]1[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OCCCc1ncccc1OCc1ccccc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCc1ncccc1OCc1ccccc1
Reaction time: 144 h

Procedure:
A mixture of 3-(phenylmethoxy)-2-pyridinepropanol (1.4 g), 1,6-dibromohexane (4 ml), 40% aqueous sodium hydroxide (4 ml) and TAB (100 mg) was stirred vigorously for 6 days. Water (10 ml) was added and the mixture was extracted with ether (3×10 ml). The ether extracts were washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with cyclohexane followed by cyclohexane/ethyl acetate (4:1) to give the title compound as an orange oil (1.0 g) t.l.c. (cyclohexane/ethyl acetate 4:1) Rf 0.25.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[NH:9][N:8]=[CH:7]2.[CH2:14]1COCC1>>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[N:9]([CH3:14])[N:8]=[CH:7]2
Reactant: Fc1cc2[nH]ncc2cc1Br
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cn1ncc2cc(Br)c(F)cc21
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (8.84 g, 221 mmol) in THF (50 mL) was added dropwise a solution of 5-bromo-6-fluoro-1H-indazole (CAS 105391-70-6, 44.1 g, 201 mmol) in THF (200 mL) at 5° C. After 15 min at 5° C., Mel (31.7 mL, 221 mmol) was added at 5° C. and the RM was stirred between 0° C. and 5° C. for 1.5 h. The reaction was quenched with 0.5 M HCl and extracted with EtOAc. The organic phases were combined, washed with brine, dried over Na2SO4 and evaporated under vacuo. The 2 isomers formed were separated by MPLC with heptane and EtOAc to afford the title compound as a yellow solid (tR 5.07 min (conditions 1), NMR in DMSO-d6: 8.14 (d, 1H); 8.04 (s, 1H); 7.79 (d, 1H); 4.00 (s, 3H)).
Reaction SMILES: [CH2:1]([C:13]1[NH:17][N:16]=[N:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1NN=NN=1)CCCCCCCCC.[CH2:33]([O:35][C:36](=[O:41])[C:37](Br)([CH3:39])[CH3:38])[CH3:34].BrC1C=CC=CC=1CC(OCC)=O>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([C:37]([CH3:39])([CH3:38])[C:36]([O:35][CH2:33][CH3:34])=[O:41])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn[nH]1
Reactant: CCOC(=O)C(C)(C)Br
Agent: CCCCCCCCCCc1nnn[nH]1
Agent: CCOC(=O)Cc1ccccc1Br
Product: CCCCCCCCCCCCc1nnn(C(C)(C)C(=O)OCC)n1

Procedure:
When in the general procedure of Example 71 an appropriate amount of 5-dodecyl-1H-tetrazole was substituted for 5-decyl-1H-tetrazole and an appropriate amount of ethyl-2-bromoisobutyrate was substituted for ethyl 2-bromophenylacetate, the title compound was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[O:14][C:8]1([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH2:7][C:6]2=[O:18].[C:19]([O:24][C@@H:25]([C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C(O)(C)C>[C:19]([O:24][C@@H:25]([C:27]1[N:28]=[C:29]([N:11]2[CH2:12][CH2:13][C:8]3([CH2:7][C:6](=[O:18])[C:5]4[C:15](=[CH:16][CH:17]=[C:3]([Cl:2])[CH:4]=4)[O:14]3)[CH2:9][CH2:10]2)[CH:30]=[CH:31][N:32]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(Cl)cc21
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCC3(CC2)CC(=O)c2cc(Cl)ccc2O3)n1
Yield: 100 %

Procedure:
To a solution of 6-chloro-spiro[chroman-2,4′-piperidin]-4-one hydrochloride (prepared according to the method of Example 78, Step A, 175 mg, 0.61 mmol) in isopropanol (5 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 160 mg, 0.70 mmol) followed by triethylamine (0.29 mL, 2.1 mmol). This mixture was stirred at reflux for 1.5 h, concentrated, and purified by flash column chromatography (1% methanol/chloroform) to give 270 mg (100%) of the title compound of Example 78, Step B as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ8.19 (d, 1H), 7.83 (d, 1H), 7.44 (dd, 1H), 6.97 (d, 1H), 6.37 (d, 1H), 5.64 (q, 1H), 4.18 (app s, 2H), 3.34 (t, 2H), 2.72 (s, 2H), 2.37 (t, 2H), 2.10 (d, 2H), 1.71-1.60 (c, 4H), 1.55 (d, 3H), 0.94 (t, 3H); MS (APCI) 444, 446 (MH+).