Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][NH2:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:57](Cl)(=[O:59])[CH3:58]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][NH:49][C:57](=[O:59])[CH3:58])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCN)CCC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCNC(C)=O)CCC3)cc1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To an ice-cooled solution of 0.070 g (0.104 mmol) of (3R,4R)-3-[1-(3-amino-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 10(c)] and 0.013 g (0.125 mmol, 1.2 equiv.) of triethylamine in 1 ml of dichloromethane was added dropwise 0.009 g (0.114 mmol, 1.1 eqiuv.) of acetyl chloride. The reaction was allowed to warm to room temperature, poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 20 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using ethyl acetate as the eluent and yielded 0.068 g (0.095 mmol, 91.3% of theory) of (3R,4R)-3-[1-(3-acetylamino-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 716 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1C(C)CCN>>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:1][CH2:12][CH2:11][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)=[CH:15]1
Reactant: CC(CCN)c1cc2ccccc2[nH]1
Reactant: ClCCOc1cccc2[nH]ccc12
Product: CC(CCNCCOc1cccc2[nH]ccc12)c1c[nH]c2ccccc12
Yield: 43 %

Procedure:
This compound was prepared in the manner described above for Example 5 using 2-(1H-indol-4-yloxy)ethylchloride and 3-indolyl-butylamine in 43% yield as an off-white solid: mp 70-73° C.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:38])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:37])[CH3:36])[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[NH2:11][C:12]1[C:13](=[O:38])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:36])[CH3:37])[C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (10 g) and anisole (6.6 g) in dichloromethane (100 mL) at 0° C. was added trifluoromethanesulphonic acid (9 mL, 15.3 g) while maintaining the temperature below 2° C. The reaction mixture was allowed to warm to room temperature in 30 min and kept at room temperature for a further 45 min before saturated aqueous sodium bicarbonate was added slowly to pH 7. Ethyl acetate was added, the phases separated and the aqueous phase extracted further with ethyl acetate. The combined organic extract was washed (brine), dried (MgSO4) and evaporated. The crude product was purified by trituration with hexane followed by trituration with diethyl ether to give the title product (which can be recrystallized from dichloromethane/hexane) as a white solid (4.85 g); TLC: Rf =0.40, ethyl acetate; 300 MHz NMR: 0.78-0.91 (m,6), 2.07-2.30 (m,1), 4.39 (d,1), 4.49 (d,1), 4.61 (t,1), 5.17 (s,1), 5.98 (d,1), 6.51 (d,1), 7.28-7.41 (m,5), 8.68 (d,1); MS: m/z=396(M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[Br:10]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:10][C:7]1[C:2]([NH2:1])=[N:3][C:4]([Cl:9])=[N:5][C:6]=1[Cl:8]
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cl)nc(Cl)c1Br
Temperature: 25 °C

Procedure:
2 g (12.2 mmol) of 4-amino-2,6-dichloropyrimidine were dissolved in 10 ml of DMF. To this solution were added 2.6 g (14.6 mmol) of N-bromosuccinimide. The reaction mixture was stirred at room temperature over night. The solution was poured onto 200 ml of cool water. The formed precipitate was filtered and washed with water. The product was obtained 2.7 g (91.9%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:23](O)=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:27]1[CH2:32][CH2:31][C:30]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)[CH2:29][CH2:28]1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([C:23]([N:27]1[CH2:32][CH2:31][C:30]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)[CH2:29][CH2:28]1)=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(C=Cc3ccccc32)CC1)OCc1ccccc1
Reaction time: 12 h
Yield: 79.5 %

Procedure:
To a solution of N-benzyloxycarbonyl-(D)-tryptophan (1.69 g, 5.0 mmole) in 70 mL of chloroform at room temperature was added spiro[1H-indene-1,4'-piperidine]hydrochloride (J. Med. Chem. 1992, 35, 2033)(1.21 g, 5.5 mmole), triethylamine (0.73 mL, 5.25 mmole) followed by 1-hydroxybenzotriazole hydrate (0.74 g, 5.5 mmole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.05 g, 5.5 mmole). After 12 hours at room temperature, the mixture was diluted with methylene chloride and then washed sequentially with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatatron (hexanes/ethyl acetate=1/1) to give 2.01 g (79%) of the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:13][C:7]1[CH:6]=[C:5]2[C:4]([C:3]([OH:2])=[C:16]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=3)[C:15](=[O:25])[NH:14]2)=[CH:9][C:8]=1[N+:10]([O-:12])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1NC(=O)Cc1cc(C)cc(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2c(O)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of 4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-5-nitrobenzoic acid methyl ester (1.17 g in 10 mL dry tetrahydrofuran) at 0° C. was added dropwise a solution of sodium bis(trimethylsilyl)amide (7.8 mL of a 1.0M solution in tetrahydrofuran) and the mixture warmed to room temperature. After 2 hours, the reaction was quenched by the addition of 100 mL iced 6N hydrochloric acid. The slurry was stirred for 10 minutes then filtered and washed (2×) with ice water and then cold acetonitrile. The residue was dried overnight at 45° C. to give the title compound (970 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]([F:17])[F:16])[CH2:13][CH2:12][O:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]3([CH:15]([F:17])[F:16])[CH2:13][CH2:12][O:11][C:10]([NH2:14])=[N:9]3)[CH:7]=2)[CH:23]=[N:24][CH:25]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: NC1=NC(c2cc(Br)ccc2F)(C(F)F)CCO1
Product: NC1=NC(c2cc(-c3cncc(Cl)c3)ccc2F)(C(F)F)CCO1

Procedure:
In a manner analogous to that described in Example 31, the cross-coupling reaction of 4-(5-bromo-2-fluorophenyl)-4-(difluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (intermediate A6.12) and 5-chloropyridin-3-ylboronic acid yielded the title compound as a light brown solid. MS (ISP): m/z=356.0 [M+H]+ and 358.0 [M+2+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:20][CH2:19][C:15]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]1.[CH:28](N)=O.C(OCC)(=O)C>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][N:12]1[CH2:20][CH2:19][C:15]2([N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:28][NH:18][C:16]2=[O:17])[CH2:14][CH2:13]1
Reactant: NC=O
Reactant: NC(=O)C1(Nc2ccccc2)CCN(CC2=Cc3ccccc3CC2)CC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NCN(c2ccccc2)C12CCN(CC1=Cc3ccccc3CC1)CC2
Temperature: 170 °C

Procedure:
A mixture of 1-[(3,4-dihydro-2-naphthalenyl)methyl]-4-anilino isonipecotamide (5.0 g) and formamide (18 g) is heated for 12 hours at 170° C. The reaction mixture is cooled, diluted with water (100 ml), and extracted with chloroform. The chloroform solution is dried over sodium sulfate and concentrated to give crude product. Trituration with ethyl acetate produces the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH:19][NH2:20])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]=[C:23]=[S:24]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]([NH:19][NH:20][C:23]([NH:22][CH3:21])=[S:24])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CN=C=S
Solvent: Cc1ccccc1
Product: CNC(=S)NNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 95.9 %

Procedure:
N-Benzyloxycarbonyl-4-(hydrazinocarbonyl)piperidine (231 g) was dissolved in toluene (500 ml) and a solution of methyl isothiocyanate (90 g) in toluene (50 ml) was added with stirring. After lhr the resulting precipitate was separated, washed with ether and dried to give the title compound (280 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][C:13]([S:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[N:18][S:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Reaction time: 8 h

Procedure:
To a solution of 1,4-dioxa-spiro[4.5]decan-8-one (Aldrich, 4.07 g, 26.1 mmol) and 2-methyl-propane-2-sulfinic acid amide (Aldrich, 3.16 g, 26.1 mmol) in THF (20 mL) was added Ti(OEt)4 (Aldrich, 10.8 mL, 52.2 mmol) at room temperature. The reaction was stirred overnight and quenched with ˜5 mL water until precipitation completed. The solid was filtered off and washed with additional ethyl acetate. The combined filtrate was dried over anhydrous Na2SO4, filtered, concentrated and the residue was purified by a CombiFlash® system using hexanes and ethyl acetate as eluent (from pure hexanes to pure ethyl acetate) to afford the title compound as colorless oil.
Reaction SMILES: [OH:1][C@H:2]1[CH:16]=[C:15]2[C@:5]([CH3:17])([CH2:6][C:7]3[C:8](=[CH:14]2)[O:9][C:10](=[O:13])[C:11]=3[CH3:12])[C@@H:4]([CH3:18])[C@H:3]1[O:19][C:20](=[O:23])[CH2:21][CH3:22].N1C=CC=CC=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>>[CH:30]1([C:33]([O:1][C@H:2]2[CH:16]=[C:15]3[C@:5]([CH3:17])([CH2:6][C:7]4[C:8](=[CH:14]3)[O:9][C:10](=[O:13])[C:11]=4[CH3:12])[C@@H:4]([CH3:18])[C@H:3]2[O:19][C:20](=[O:23])[CH2:21][CH3:22])=[O:34])[CH2:32][CH2:31]1
Reactant: CCC(=O)O[C@H]1[C@@H](O)C=C2C=C3OC(=O)C(C)=C3C[C@]2(C)[C@H]1C
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: CCC(=O)O[C@H]1[C@@H](OC(=O)C2CC2)C=C2C=C3OC(=O)C(C)=C3C[C@]2(C)[C@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
The title compound (70 mg, 96%) was prepared in the same manner as in Example A3, except that the compound (60 mg, 0.19 mmol) prepared in Example A2, anhydrous pyridine (151 μl, 1.87 mmol), and cyclopropanecarbonyl chloride (68 μl, 0.75 mmol) were stirred at 25° C. for 30 min and the purification was performed by column chromatography on silica gel (toluene:ethyl acetate=20:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([S:26][CH2:27][CH3:28])=[N:24][CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([CH2:27][CH3:28])=[O:37])=[N:24][CH:25]=3)=[CH:18][CH:19]=2)[N:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1
Solvent: CC(Cl)Cl
Product: CCS(=O)c1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-[4-(2-ethylthiopyridin-5-yl)phenyl]oxazoline (Ex. No. 39; 0.60 g, 1.5 mmol) was stirred for 5 hours at 20° C. with 3-chloroperbenzoic acid (0.41 g, 1.7 mmol) in dichloroethane (10 ml). After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-ethylsulfinylpyridin-5-yl)phenyl]oxazoline was obtained, 0.21 g, colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH:13]=[CH:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][C:17](=[O:23])[C:16]=1[CH3:24])=[CH:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].P(=O)([O-])[O-]>>[CH3:1][C:2]([CH:13]=[CH:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][C:17](=[O:23])[C:16]=1[CH3:24])=[C:3]=[CH:4][P:5](=[O:12])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11]
Reactant: CCOP(=O)(CC=C(C)C=CC1=C(C)C(=O)CCC1(C)C)OCC
Agent: O=[PH]([O-])[O-]
Product: CCOP(=O)(C=C=C(C)C=CC1=C(C)C(=O)CCC1(C)C)OCC

Procedure:
In accordance with a procedure suggested by B. C. Ranu, et al., J. Org. Chem., 63, 5250 (1998), the following experiment was conducted: to a 25 mL 1-neck reaction flask fitted with a reflux condenser connected to an apparatus similar to that described by Johnson and Schneider [Org. Synth., 30, 18 (1950)] so that the mixture in the flask could be protected from atmospheric moisture, et al. throughout the course of the reaction were added 246 mg (0.70 mmole) of allenic phosphonate produced in accordance with Example VIII, 2 mg of hydroquinone (or other suitable antioxidant), 6.0 mL of methyl alcohol (HPLC-grade, purchased from Aldrich Chemical Co.), 54 mg (0.86 mmole) of ammonium formate, and 42 mg of 10% Pd-C (purchased from Aldrich Chemical Co.). After sweeping the system briefly with nitrogen gas, the mixture was heated, with vigorous stirring, at 60-65° C. (external oil bath temperature) for 7 hours. After cooling the mixture to room temperature, the product was isolated by dilution of the reaction mixture with 50 mL of 4:1 (v/v) ether:dichloromethane and removal of the palladium catalyst by filtration through a small pad of Hytlo Super-Cel® filtering aid. The filtrate was subsequently washed with saturated brine (2×50 mL), then dried over anhydrous magnesium sulfate and filtered. Removal of the ether and dichloromethane by evaporation at reduced pressure afforded 186 mg (75% yield) of an unsaturated phosphonate identified as 3-methyl-5-(2,6,6-trimethyl-3-oxocyclohex-1-enyl)-2,4-pentadienylphosphonic acid, diethyl ester, by IR and proton NMR (recorded at 400 MHz) analysis. IR analysis of this unsaturated phosphonate indicated that the double bond between C-1 and C-2 had been reduced [i.e., lack of absorption at 1935 cm-1 arising from the allenic moiety (C=C=C)]. The proton NMR spectrum exhibited two doublets (J=16 Hz) at δ 6.256 and 6.164 (2 vinyl H's at C-4 and C-5), a multiplet at δ 5.61 (C-2 vinyl H), a doublet of doublets (J=23.1, 8.1 Hz) at δ 2.761 (CH2P), and a triplet (J=6.9 Hz) at δ 2.505 (CH2C=O).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)CCC.[Li+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnccn2)c2c(N)ncnc21
Temperature: 120 °C
Yield: 24.8 %

Procedure:
3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (Intermediate D2a, 60 mg, 0.118 mmol), 2-(tributylstannyl)pyrazine (0.072 mL, 0.236 mmol), Pd(PPh3)4, (13.61 mg, 0.012 mmol) and LiCl (4.99 mg, 0.118 mmol) were reacted in dioxane (1.2 mL), purged under argon and heated at 120° C. overnigth. The reaction was quenched by the addition of 1M HClaqueous (2 ml), and the solids collected by filtration. The solid crude was straightforward purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile (prior to drying 5 mL of 2M HClaqueous was added). The resulting white solid was triturated in Et2O. to give (13.5 mg, 24.8%) the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:27][CH:28]=O)[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=O)C.[C:30]1([C@H:36]([NH2:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[O-]S([O-])(=O)=O.[Mg+2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[O:3]=[C:4]1[C:6]2([CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH2:8][CH2:7]2)[CH2:27][CH2:28][N:38]1[C@@H:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:37]
Reactant: CCOC(=O)C1(CC=O)CCC(NS(=O)(=O)c2ccc(-n3cccn3)cc2)CC1
Reactant: C[C@@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Product: C[C@H](c1ccccc1)N1CCC2(CCC(NS(=O)(=O)c3ccc(-n4cccn4)cc3)CC2)C1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
1-(2-oxo-ethyl)-4-(4-pyrazol-1-yl-benzenesulfonylamino)-cyclohexanecarboxylic acid ethyl ester (Intermediate 114, 40 mg, 0.095 mmol) and (R)-1-phenylethanamine (0.036 ml, 0.286 mmol) were dissolved in DCE (2 ml). MgSO4 was added (20-30 mg) followed by NaBH(OAc)3 (60.6 mg, 0.286 mmol). The reaction mixture was stirred overnight at room tempereature, then further DCE was added, and the reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated in vacuo, and the crude material taken up in DCM, and washed with water (×2). The organic layer was concentrated in vacuo, and the resultan crude oil was purified via normal phase chromatography using biotage SP1, with 25+S column, using a calculated gradient from TLC of 50% EtOAc in heptane to yield the title compound as a white solid (29 mg, 64%) as a mixture of 95% “trans” (as shown above): 5% “cis”. MS MH+ 479.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]C(OC(C)(C)C)=O)[C:5](N1C=CN=C1)=[O:6].[OH-].[Na+].[NH2:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45]>C(Cl)(Cl)Cl>[OH:46][CH:43]([CH2:44][OH:45])[CH2:42][NH:41][C:5](=[O:6])[C:4]1[CH:12]=[CH:13][C:14]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNc1ccc(C(=O)n2ccnc2)cc1F
Reactant: NCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NCC(O)CO)cc1F
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{3-fluoro-4-[N-(tert-butyloxycarbonyl)hexadecylamino]benzoyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield light yellow crystals of N-(2,3-dihydroxypropyl)-3-fluoro-4-(hexadecylamino)benzamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:7]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: C1CCNC1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccnc(Cl)c1)C2
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccnc(N3CCCC3)c1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(2-chloropyridine-4-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triaza-cyclopenta[b]naphthalene and pyrrolidine. 1H NMR (400 MHz, CHCl3-d): δ 8.30 (d, 1H), 7.44-7.36 (m, 3H), 7.15 (t, 2H), 6.76 (dd, 1H), 6.65 (s, 1H), 6.29 (d, 1H), 4.24-4.13 (m, 1H), 3.91 (dd, 1H), 3.49 (t, 4H), 3.36 (s, 4H), 3.16-3.07 (m, 2H), 2.78-2.68 (m, 1H), 2.59-2.51 (m, 1H), 2.38 (d, 1H), 2.28-2.20 (m, 2H), 2.05 (t, 4H).