Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[NH:12]C(=O)OC(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[NH2:12]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CO[C@H]1Cc2ccccc2[C@H]1N
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
To tert-butyl [(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]carbamate (253 mg, 0.961 mmol) was added a 4.00 M solution of hydrochloric acid in 1,4-dioxane (5.00 mL) and the mixture was stirred for 10 min, after which a white solid crashed out. The suspension was concentrated in vacuo and co-evaporated with toluene to afford a white solid, which was dissolved in water. The solution was adjusted to pH 10 via addition of sodium carbonate. The mixture was then extracted with diethyl ether (3×30 mL) and the organic extracts were concentrated in vacuo to afford the title compound (150 mg, 99%). LC/MS: Rt=0.85 min, ES+ 164 (AA standard).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[OH:18])[C:6](=[O:19])[C:5]=2[CH:4]=1.C[O-].[Na+].Cl.Cl[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>CO.ClC1C=CC=CC=1>[CH2:26]([N:27]([CH2:30][CH3:31])[CH2:28][CH2:29][O:18][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:13]1[C:14]([O:16][CH3:17])=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]2=[O:19])[CH3:25]
Reactant: CCN(CC)CCCl
Reactant: COc1cc(OC)c2c(c1)C(=O)c1cccc(O)c1-2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Clc1ccccc1
Product: CCN(CC)CCOc1cccc2c1-c1c(OC)cc(OC)cc1C2=O
Yield: 64.9 %

Procedure:
Similar to example 3D1, prepare a solution of 2,4-dimethoxy-5-hydroxy-fluoren-9-one (0.33 g, 1.3 mmol) in methanol (8 mL) and 24 mL chlorobenzene with sodium methoxide (0.11 g, 2.0 mmole), and react the free base of 2-chloro-ethyl-diethyl amine hydrochloride 2.1 g (12 mmole) in order to obtain 0.30 g of the title compound as a reddish-orange powder. m.p. 178° C.-180° C. Analysis calculated for C21H25NO4.HCl: C, 64.36; H, 6.69; N, 3.58. Found: C, 63.99; H, 6.75; N, 3.62.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:17]1[O:18][CH2:19][CH2:20][N:21]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C>C(OCC)C>[C:1]([O:5][CH2:19][CH2:20][NH:21][C:17](=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCCCCCCCCCCC1=NCCO1
Reactant: C=CC(=O)O
Solvent: CCOCC
Product: C=CC(=O)OCCNC(=O)CCCCCCCCCC
Temperature: 80 °C

Procedure:
51.99 g acrylic acid and 0.3 g BHT were heated in a round-bottom flask to 80° C. Under stirring, 81.3 g molten undecyl oxazoline was slowly added during 1 hour maintaining the reaction temperature at 80° C . After stirring for another hour at 80° C. the reaction mixture was poured into 200 ml diethyl ether and washed with water, twice with a 10% sodium bicarbonate solution and twice with water. After drying on magnesium sulfate, filtration and evaporation in vacuo of the solvent 100.5 g of N-acryloxyethylundecylamide was obtained.
Reaction SMILES: [NH2:1][CH2:2][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.Cl[S:46]([C:49]1[CH:57]=[CH:56][C:52]([C:53]([OH:55])=[O:54])=[CH:51][CH:50]=1)(=[O:48])=[O:47].CCN(C(C)C)C(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:32]([O:31][C:29]([C:28]1[CH:36]=[CH:37][C:25]([C:12]2[C:13]([CH3:24])([CH3:23])[C@H:14]3[C@:9]([CH3:38])([CH2:10][CH:11]=2)[C@@H:8]2[C@:17]([CH3:22])([C@@:18]4([CH3:21])[C@H:5]([CH2:6][CH2:7]2)[C@H:4]2[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:3]2([CH2:2][NH:1][S:46]([C:49]2[CH:50]=[CH:51][C:52]([C:53]([OH:55])=[O:54])=[CH:56][CH:57]=2)(=[O:48])=[O:47])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:26][CH:27]=1)=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNS(=O)(=O)c3ccc(C(=O)O)cc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aminomethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (25 mg, 0.042 mmol) in DCM (2 ml) was added 4-(chlorosulfonyl)benzoic acid (9.19 mg, 0.042 mmol) and DIPEA (7.28 μl, 0.042 mmol). The resulting mixture was stirred for 48 h at rt. The mixture was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was used in the next step with no additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9]2)=[N:6][CH:7]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:21][CH:18]3[CH2:20][CH2:19]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc(Br)cn2)C1
Reactant: NC1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(N2CC[C@@H](NC3CC3)C2)nc1
Reaction time: 6 h
Yield: 61.2 %

Procedure:
Dissolve methanesulfonic acid (S)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl ester (3.07 g, 9.48 mmol) and cyclopropylamine (1.7 mL, 23.68 mmol) in THF (20 mL). Microwave the mixture at 130° C. for 6 h. Dilute the mixture with EtOAc (100 mL) and wash with saturated NaHCO3 (25 mL). Dry the organic portion over Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with a gradient of 75-100% EtOAc/hexane to give 1.638 g (61%) of the title compound. LC-MS/ES m/z (79Br) 283.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[N:5][N:4]2[CH2:8][CH2:9][CH2:10][C:3]=12.[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.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>[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:2]2[C:6]([CH3:7])=[N:5][N:4]3[CH2:8][CH2:9][CH2:10][C:3]=23)[CH:15]=1
Reactant: Cc1nn2c(c1Br)CCC2
Reactant: COC(=O)c1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#N)c(-c2c(C)nn3c2CCC3)c1
Temperature: 95 °C
Yield: 49.8 %

Procedure:
In a pressure sealed flask a suspension of 3-bromo-2-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (1.01 g, 5.0 mmol), 4-cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (1.8 g, 6.25 mmol), and K3PO4 (2.65 g, 12.5 mmol) in dioxane (50 mL) was degassed by bubbling N2 for 30 m at room temperature. After the addition of tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mmol) the reaction flask was sealed and the contents heated to 95° C. for 5 h. After cooling the reaction mixture was diluted several fold with EtOAc, and washed with dilute aqueous NaHCO3 followed by brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified over normal phase silica starting with 100% DCM for 5 m and then increasing to 10% MeOH in DCM over 25 m to give the desired product as a yellow solid (0.70 g, 2.49 mmol). MS m/z 282.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.[NH2:36][C@@H:37]([C:41]([O:43]C(C)(C)C)=[O:42])[CH:38]([CH3:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([NH:36][C@@H:37]([C:41]([OH:43])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:32])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 0.08 h

Procedure:
[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid, (50.0 mg, 0.10 mmol) was dissolved in DCM (2 ml). tert-Butyl D-valinate hydrochloride (28.4 mg, 0.14 mmol) and N-methylmorpholine (3.0 μl, 0.31 mmol) were added. After 5 minutes, TBTU (43.7 mg, 0.14 mmol) was added and the mixture was stirred overnight. The intermediate tert-butylester of the title compound was confirmed. M/z: 637.1 (M−H). The solvent was removed under reduced pressure. The yellow residue was dissolved in formic acid (1.5 ml) and heated at 50° C. for 5 h. The solvent was evaporated and the residue was purified by preparative HPLC on a C8 column. A gradient from 20 to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (30.5 mg, 51%). 1H-NMR (400 MHz, DMS-d6): 0.74 (t, 6H), 1.98-2.07 (m, 1H), 3.84 (brs, 1H), 4.32 (d, 1H), 4.35 (s, 1H), 4.36 (s, 1H), 4.50 (brs, 2H), 5.16 (d, 1H), 6.96 (d, 2H), 7.10-7.17 (m, 2H), 7.19-7.24 (m, 2H), 7.31-7.38 (m, 4H), 7.66 (brs, 1H), 7.99-8.04 (m, 2H). M/z: 583.0 (M+H) and 581.0 (M−H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[N:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[Cl:26])(O)O.C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[Cl:26][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:17]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[N:3]=1)[C:21]([OH:23])=[O:22]
Reactant: Oc1ccc2nc(Cl)ccc2c1F
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc3c(F)c(O)ccc3n2)c(Cl)c1
Temperature: 95 °C
Yield: 15.7 %

Procedure:
2-Chloro-5-fluoroquinolin-6-ol (Intermediate 16, 1.0 mmol) and 4-borono-3-chlorobenzoic acid (1.1 mmol) were mixed with 5% (Ph3P)4Pd and 4.0 mmol of NaHCO3 in 20 ml 50% dioxane/water. The mixture was degassed three times by evacuation and argon filling and heated at 95° C. overnight. The reaction was diluted with 20 ml of water and filtered. The filtrate was acidified with 1N HCl to pH=4. The precipitate was filtered and washed with water, dried. The crude was purified by column using AcOH/MeOH/EtOAC (1/5/94) as solvent B and hexanes as solvent A with gradient 2 to 100%. The fractions with compound were pooled and evaporated to obtain white solid. The solid was triturated with diisopropyl ether. 50 mg of final product was obtained. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 10.55 (b, 1H), 8.47 (d, 1H), 8.01-8.03 (m, 2H), 7.79 (m, 3H), 7.56 (t, 1H). MS (ESI): m/z=316.3 [M−H]−.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>C(OCC)(=O)C>[Cl:10][C:11]1[CH:19]=[C:18]([F:20])[C:17]([N+:1]([O-:4])=[O:2])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A blend of 70% nitric acid (64.5 gm) and concentrated sulfuric acid (65 mL) was added dropwise over an hour period to a suspension of 2-chloro-4-fluoro-benzoic acid (125.0 gm, 716 mL). The white suspension was stirred mechanically for 30 minutes at ambient temperature. The thick white suspension was carefully poured into ice-water (100 mL). Ethyl acetate (800 mL) was added. The organic layer was separated, dried (MgSO4) and evaporated to dryness under vacuum to give the title compound of Step A as a white solid (156.0 gm, 99%); m.p. 134°-136° C.; IR (cm-1), C=O (1719.8). This intermediate was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2C)=[O:9])[CH:3]=1.ClC1N=CN=C(C(NC2C=CC(O)=CC=2)=O)C=1.C(N(C(C)C)C(C)C)C.[NH2:45][C:46]1[C:47]([CH3:52])=[CH:48][CH:49]=[CH:50][CH:51]=1>C(O)C>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[CH3:52])[N:7]=[CH:6][N:5]=2)=[O:9])=[CH:16][CH:15]=1
Reactant: Cc1ccccc1N
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Agent: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1Nc1cc(C(=O)Nc2ccc(O)cc2)ncn1
Temperature: 160 °C

Procedure:
A solution of 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide, Intermediate 7 (50.0 mg; 0.20 mmol) in ethanol (3 mL) was treated with N-ethyldiisopropylamine (69 μl; 0.4 mmol) and o-toluidine (Fluka, 21.5 μl; 0.20 mmol). The reaction mixture was heated at 160° C. for 3 hours under microwave irradiation. The solvents were removed in vacuo, EtOAc was added and the organic phase was washed with a citric acid solution, dried over magnesium sulfate then evaporated in vacuo. The crude product was purified by column chromatography (silica), eluting with cyclohexane containing an increasing amount of EtOAc. The title compound was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[N:6][CH:7]=1.F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl>[C:17]([C:16]1[CH:15]=[C:14]([N:11]2[CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[N:9]=[CH:10]2)[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: N#Cc1cccc(F)c1
Reactant: Fc1ccc(-c2c[nH]cn2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2cnc(-c3ccc(F)cn3)c2)c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
In a screw-cap vial, added 4-(5-Fluoro-2-pyridyl)imidazole (0.06 g, 0.30 mmol), 3-Fluorobenzonitrile (0.04 ml, 0.36 mmol), potassium carbonate (0.21 g, 1.5 mmol) and dimethylformamide (1 ml). Stirred the resulting reaction mixture at 110° C. overnight. Cooled the reaction mixture to room temperature, diluted with chloroform (50 ml), sequentially washed with water, (50 ml) and brine (50 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was triturated with 10% diethyl ether in hexanes to yield the title compound (45 mg) as a dirty yellow colored solid. 1H—NMR (CDCl3), δ (ppm): 8.43 (d, 1H), 8.04 (dd, 1H), 7.93 (dd, 2H), 7.70 (m, 4H), 7.48 (dt, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][N+:12]([O-:14])=[O:13])(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[CH3:15][C:8]([NH2:7])([CH3:16])[CH2:9][CH2:10][CH2:11][N+:12]([O-:14])=[O:13]
Reactant: CC(C)(CCC[N+](=O)[O-])NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)CCC[N+](=O)[O-]
Temperature: 25 °C
Yield: 88 %

Procedure:
To (1,1-Dimethyl-4-nitro-butyl)-carbamic acid tert-butyl ester (1.0 g, 4.0 mmol) in 25 mL CH2Cl2 at −10° C. was added 2.5 mL TFA. The mixture was warmed to rt and monitored by TLC. When judged complete by TLC analysis, the mixture was concentrated to give the 518 mg (88%) of the title compound as an orange oil: mass spectrum m/e=147 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C.[CH2:20]([P:22]([CH2:28][OH:29])(=[O:27])[O:23][CH:24]([CH3:26])[CH3:25])[CH3:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:20]([P:22]([CH2:28][O:29][S:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:11])=[O:10])(=[O:27])[O:23][CH:24]([CH3:26])[CH3:25])[CH3:21]
Reactant: CCP(=O)(CO)OC(C)C
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCP(=O)(COS(=O)(=O)c1c(Cl)cccc1Cl)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A solution of 19.6 g of 2,6-dichlorobenzenesulfonyl chloride dissolved in 70 ml of methylene chloride was added dropwise over 40 minutes to a mixture of 25 ml of methylene chloride, 15.0 ml of triethylamine, 1.0 g of DMAP, and 16.5 g of O-isopropyl P-ethyl(hydroxymethyl)phosphinate, (Example 22, Method A). The addition caused a mild exotherm and the reaction was allowed to stir at room temperature overnight. The reaction mixture was then washed with two 50 ml portions of water, the phases separated, the organic phase dried with magnesium sulfate, filtered, and concentrated to yield 19.6 g of the desired product as a yellow oil. The crude product was diluted with 10 ml of methylene chloride and flash chromatographed using blends of ethyl acetate and hexanes. Similar fractions were combined and rechromatographed to yield 0.95 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Br)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23]>CO.C(N(CC)CC)C>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: COC(=O)CN
Reactant: CCOP(=O)(Cc1ccccc1CBr)OCC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1ccccc1CNCC(=O)OC)OCC

Procedure:
A solution of the diethyl[[2(bromomethyl)phenyl]methyl]phosphonate (Example A) (0.9 g, 2.8 mmol) in methanol (25 ml) and triethylamine (5 ml) is treated with glycine methyl ester hydrochloride (0.71 g, 5.6 mmol) and heated at reflux in an oil bath for 19 hours. The solvent is removed in vacuo and the residue dissolved in water and extracted with chloroform. The chloroform layer is dried over magnesium sulfate, filtered, and evaporated. The oily residue is purified via silica gel chromatography (2-4% methanol in chloroform as eluant).
Reaction SMILES: [NH2:1][C:2]1[C:31]([CH:32]=C)=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:34].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.C[OH:58]>>[NH2:1][C:2]1[C:3]([F:34])=[CH:4][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:26])([CH3:25])[CH3:27])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:30][C:31]=1[CH:32]=[O:58]
Reactant: CO
Reactant: C=Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(C=O)c4)CS(=O)(=O)C[C@@H]32)c1
Temperature: 25 °C

Procedure:
A solution of (3aR*,7S*,7aS*)-7-(4-amino-3-fluoro-5-vinyl-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (0.215 g, 0.44 mmol) in CH2Cl2-MeOH 4:1 (10 mL) was ozonized at −78° C. until the educt disappeared. After addition of PPh3 (0.139 g, 0.53 mmol) the reaction mixture was allowed to warm to 25° C. and the solvents were removed under reduced pressure. The title compound was obtained after flash-chromatography on silica gel (hexane-EtOAc 2:1) as white solid: ESIMS [M−H]−=487.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[C:6]([Cl:14])[C:7]([Cl:13])=[C:8]([OH:12])[CH:9]=2)[C:4]1=[O:15])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[O:15]=[C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:12][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:7]([Cl:13])[C:6]=2[Cl:14])[CH2:11][CH:3]1[CH2:1][CH3:2]
Reactant: CCC1Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC)C2
Temperature: 60 °C

Procedure:
A mixture of 2-ethyl-5-hydroxy-6,7-dichloro-1-indanone (9.8 g., 0.04 mole), dimethylformamide (30 ml.), potassium carbonate (12.5 g., 0.09 mole) and ethyl bromoacetate (15 g., 0.09 mole) is stirred and heated on a water bath at 60° C. for one hour. The reaction mixture is poured into ice water (200 ml.) and extracted with two 50 ml. portions of ether. The ether extract is washed with water, dried over magnesium sulfate and the ether distilled at reduced pressure. The ethyl (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetate thus obtained melts at 116°-118° C. after recrystallization from ethyl alcohol.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].N12CCCN=C1CCCCC2.C1(P([N:57]=[N+:58]=[N-:59])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([N:57]=[N+:58]=[N-:59])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C(N=[N+]=[N-])c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Temperature: 50 °C
Yield: 55.7 %

Procedure:
A mixture of 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile (3 g, 7.22 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (2.3 mL, 15.2 mmol), diphenylphosphoryl azide (3.3 mL, 15.2 mmol) and tetrahydrofuran (20 mL) is stirred at 50° C. 2 hr. The mixture is concentrated and the crude residue is purified via silica chromatography eluting with hexanes to 7:3 hexanes:ethyl acetate to give the title compound 1.77 g, 56% as a white solid. LCMS M−1 439.