Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:39])[C@@H:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]([NH:15][C@H:16]([C:26](O)=[O:27])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:40]([S:59][CH2:60][C@@H:61]([C:63]([NH2:65])=[O:64])[NH2:62])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:39])[C@@H:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][C@H:16]([C:26]([NH:62][C@H:61]([C:63]([NH2:65])=[O:64])[CH2:60][S:59][C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:27])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])=[CH:29][CH:30]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.23 g (2.23 mmol) of the compound from example 24A was dissolved in 25 ml dichloromethane. 0.81 g (2.23 mmol) S-Trityl-L-cysteinamide, 0.39 ml (2.23 mmol) N,N-diisopropylethylamine and 0.85 g (2.23 mmol) HATU were added. The reaction mixture was stirred at room temperature for 3 h. From the reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 70 ml silica gel. Solvents used were dicloromethane/methanol 20/1 to dichloromethane/methanol 5/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 2.38 g (2.03 mmol, 91% of theory, 76% purity) of the desired product.
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([OH:17])[CH:9]=[C:10]([C:12]([Cl:16])=[C:13]([Cl:15])[Cl:14])[CH:11]=1)=[C:3]([Cl:5])[Cl:4].O[CH2:19][NH:20][C:21](=[O:24])[CH2:22][Cl:23].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:23][CH2:22][C:21]([NH:20][CH2:19][C:7]1[C:6]([C:2]([Cl:1])=[C:3]([Cl:5])[Cl:4])=[CH:11][C:10]([C:12]([Cl:16])=[C:13]([Cl:14])[Cl:15])=[CH:9][C:8]=1[OH:17])=[O:24]
Reactant: Oc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Reactant: O=C(CCl)NCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCl)NCc1c(O)cc(C(Cl)=C(Cl)Cl)cc1C(Cl)=C(Cl)Cl
Temperature: 25 °C

Procedure:
A mixture of 0.352 g (1.0 mmol) of the product of Step D and 0.123 g (1.0 mmol) of N-hydroxymethyl-2-chloroacetamide was added in portions to a vigorously stirred solution of 0.9 mL acetic acid and 0.1 mL (98%) sulfuric acid at 0-10° C. The reaction mixture was allowed to warm to room temperature, and stirring was maintained for a total of 4 days. The reaction mixture was poured into ice-water, neutralized with saturated aqueous NaHCO3 solution and extracted into CH2Cl2. The organic extracts were combined, washed with brine, dried Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5-10% EtOAc in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([OH:30])[CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([OH:28])([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)[C:17]([F:20])([F:19])[F:18]>>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([OH:28])([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)[C:17]([F:19])([F:18])[F:20])[O:30][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2]
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: CC(=O)OCCBr
Product: CC(=O)OCCOc1ccc(C(C)C(O)(c2cnc(C)cn2)C(F)(F)F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 74 from 2-bromoethyl acetate and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=433.1 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:17])[OH:16])=[N:10][C:9]=2[C:8]([O:18][CH3:19])=[CH:7][CH:6]=1)[OH:4]>C(Cl)(Cl)Cl.O=[Mn]=O>[Br:1][CH2:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:16])[OH:17])=[N:10][C:9]=2[C:8]([O:18][CH3:19])=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(C(O)CBr)c2sc(NC(=O)O)nc12
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)CBr)c2sc(NC(=O)O)nc12
Yield: 73 %

Procedure:
1.6 g of rac-[7-(2-bromo-1 -hydroxy-ethyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyll ester (0.0044 Mol) were dissolved in CHCl3 (100 ml) and treated with 3.8 g of MnO2 (0.044 Mol) for 3 hrs. at 70° C. The hot reaction mixture was filtered and subsequently concentrated. The crude product was crystallized from Et2O to yield the title compound as a beige solid (73%); F.p.: 250-260° C. (dec.).
Reaction SMILES: [CH2:1]([S:8][C:9](=[S:15])[NH:10][CH2:11][C:12](Cl)=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].S(Cl)([Cl:24])(=O)=O>ClCCl>[CH2:1]([S:8][C:9]1[S:15][C:12]([CH2:13][Cl:24])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cl)CNC(=S)SCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 g of (2-chloro-allyl)-dithiocarbamic acid benzyl ester and 4.1 g of sodium hydrogen carbonate are placed in 100 ml of dichloromethane and cooled in an ice bath. In the course of 3 minutes, a solution of 3.2 g of sulfuryl chloride in 10 ml of dichloromethane is added, and when the addition is complete the ice bath is removed. The mixture is stirred at room temperature for 2 hours and filtered off with suction, and the filtrate is concentrated by evaporation. The residue crystallises after the addition of diethyl ether. Filtration yields 2-benzylsulfanyl-5-chloromethyl-thiazole having a melting point of 129-131° C. in the form of the hydrochloride. Extraction of the mother liquor with semi-saturated aqueous sodium hydrogen carbonate solution and removal of the ether by distillation yield 2-benzylsulfanyl-5-chloromethyl-thiazole having a melting point of 57-61° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.ClCCl.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>O>[C:29]([O:19][CH2:18][CH2:17][NH:16][C:14]([NH:13][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=1)=[O:15])(=[O:33])[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)C(=O)Cl
Reactant: O=C(NCCO)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)OCCNC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
In a 0.3-l four-necked flask equipped with a dropping funnel, a reflux condenser, a thermometer and a mixing blade were placed 18.0 g (0.0666 mol) of N-(3,5-dinitrophenyl)-N-(2-hydroxyethyl)urea (compound 11) and 5.27 g (0.0666 mol) of pyridine. Thereto was added 150 ml of dichloromethane. The mixture was stirred and became a yellow suspension. While the flask was being cooled with ice water, the flask contents were stirred. Thereto was dropwise added 8.52 g (0.0799 mol) of isobutyryl chloride. After the dropwise addition, the flask was immersed in an oil bath of 40° C. and the flask contents were stirred for 1 hour. Then, the flask contents were cooled to room temperature. Thereto was added 50 ml of water, and the mixture was stirred for several minutes. All the flask contents were transferred into a separating funnel for separation of the aqueous layer. The organic layer taken out was returned to the separating funnel. Thereto was added a 5% aqueous sodium carbonate solution, followed by mixing. The lower layer (organic layer) was taken out and dried over anhydrous magnesium sulfate. From the dried solution was removed dichloromethane by distillation by the use of an evaporator, whereby a solid was separated. The solid was recrystallized from a 2:1 mixed solvent consisting of methanol and water to obtain 2-(3,5-dinitrophenylureido)ethyl isobutyrate (compound 12) as a yellow powder. Yield: 20.4 g (90%) Melting point: 89-92° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[N:3]=[C:4]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=[C:6]([Cl:8])[N:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Product: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Yield: 74 %

Procedure:
U.S. Pat. No. 4,996,318 discloses that treatment of 2,4,6-trichloropyrimidine (I) with pyrrolidine (II) at 20°-25° for 4 hrs gives 2,4-di(1-pyrrolidinyl)-6-chloropyrimidine (III) in 74.0% yield. The yield of 4,6-di(1-pyrrolidinyl)-2-chloropyrimidine (IV) was not disclosed.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:10]([C:11]3C=C(C=CC=3)C#N)=[C:6]2[C:5](=[O:27])[N:4]([CH3:28])[C:3]1=[O:29].CN1C2=CN(COCC[Si](C)(C)C)C(B(O)O)=C2C(=O)N(C)C1=O.BrC1[S:56][CH:57]=[C:58]([C:60]([O:62][CH2:63][CH3:64])=[O:61])[N:59]=1>>[CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[C:10]([C:11]3[S:56][CH:57]=[C:58]([C:60]([O:62][CH2:63][CH3:64])=[O:61])[N:59]=3)=[C:6]2[C:5](=[O:27])[N:4]([CH3:28])[C:3]1=[O:29]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Agent: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Product: CCOC(=O)c1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2COCC[Si](C)(C)C)n1

Procedure:
The title compound was prepared analogously to 3-(1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Intermediate Ga, step 3) from 1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-ylboronic acid (Intermediate Ga Step 2) and commercially available ethyl 2-bromothiazole-4-carboxylate.
Reaction SMILES: C=C[C@H](O)C#[C:5][C:6]#[C:7][CH2:8][C@H:9](O)[C@@H:10]([OH:18])[CH2:11][CH2:12]CCCCC.C(Cl)(Cl)Cl>O>[CH2:12]=[CH:11][CH:10]([OH:18])[C:9]#[C:8][C:7]#[C:6][CH3:5]
Reactant: C=C[C@H](O)C#CC#CC[C@H](O)[C@@H](O)CCCCCCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CC(O)C#CC#CC

Procedure:
(S)-8-(4S,5S)-5-heptyl-2,2-dimethyl-1,3-dioxolan-4-yl)octa-1-en-4,6-diyn-3-ol, ent-panaxytriol acetonide was prepared from (3S,9S,10S)-heptadeca-1-en-4,6-diyne-3,9,10-triol, ent-panaxytriol, by the method described in Yun, H.; Chou, T. C.; Dong, H.; Tian, Y.; Li, Y-M.; Danishefsky, S. J. J. Org Chem. 2005, 70, 10375, yielding the product with: [α]19.3D-70.5 (c=0.13, CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.94 (ddd, 17.1 Hz, 10.2 Hz, 5.4 Hz, 1H), 5.47 (d, 17.1, 1H), 5.26 (d, 10.2 Hz, 1H), 4.92 (d, 5.1 Hz, 1H), 4.36 (t, 6 Hz, 1H), 3.77 (m, 2H), 2.60 (m, 2H), 1.7-1.2 (m, 12H), 1.40 (s, 6H), 0.88 (t, 6.9 Hz, 3H). LRMS (APCI+) found 319.0, [M]+, 333.04, [M+H2O]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.CNC.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1(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)C=CC=CC=1>[C:10]([CH:9]([S:8][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:13])(=[O:11])[NH2:12]
Reactant: CC(Sc1cccc(Br)c1)C(N)=O
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(Sc1cccc(-c2ccc(C(=O)O)cc2)c1)C(N)=O

Procedure:
1.0 g 2 (3-Bromo-phenoxy)-ethyl]-dimethyl-amine, 0.694 g of 4-carboxy-benzeneboronic acid, and 2.86 g potassium carbonate were stirred in a mixture of 5 ml dioxane and 5 ml water. 0.478 g tetrakis-triphenylphosphino-palladium were added under nitrogen atmosphere and the mixture was heated 85 C for 14 hrs. The mixture was diluted with 15 ml water and filtered. The filtrate was adjusted to pH 2 with conc. HCl and the precipitated product isolated by filtration.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:19][CH2:20][CH:21]=[CH:22][CH2:23]OC(=O)C)(=[O:18])[CH3:17]>O1CCCC1.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>[C:16]([O:19][CH2:20][CH:21]=[CH:22][CH2:23][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OCC=CCOC(C)=O
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCC=CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of dibenzylamine (40 g, 0.2 mol) and 2-butene-1,4-diol diacetate (105 g, 0.61 mol) dissolved in 150 ml of tetrahydrofuran (THF) is treated with tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.9 mmol) and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and the excess 2-butene-1,4-diol diacetate is removed by bulb-to-bulb distillation at 80°-90° C./1 mm. The residue is purified by eluting through a short plug of silica gel (1:1 ethyl acetate:hexanes). 1-Acetoxy-4-dibenzylamino-2-butene is obtained in a yield of 59.2 g (95%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]3[CH:2]=2)=[CH:6][C:7]=1[O:12][CH3:13]
Reactant: COc1cc(C(=O)CBr)ccc1O
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: COc1cc(-c2cn3cc(I)ccc3n2)ccc1O
Temperature: 110 °C
Yield: 31.4 %

Procedure:
490 mg (corresponding to 2.00 mmol) of 2-bromo-4′-hydroxy-3′-methoxyacetophenone and 440 mg (corresponding to 2.00 mmol) of 2-amino-5-iodopyridine were dissolved in 15 mL of acetonitrile. The resulting solution was heated under reflux in an oil bath at 110° C. for 2 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 3.0 mL of water and 1.0 mL of methanol. Then, about 6.0 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 231 mg (corresponding to 0.628 mmol) of 2-(4′-hydroxy-3′-methoxyphenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 1, Step 2).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28](S(C)(=O)=O)[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>>[F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH2:41][C:42]([F:45])([F:44])[F:43])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{1-methanesulfonyl-5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 20), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate, to give the desired product as a light yellow oil (62%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][C:11]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:10][C:9]3=[O:21])[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC1(c2ccccc2)CCN(c2nccc(Cl)n2)C(=O)O1
Product: CC1(c2ccccc2)CCN(c2nccc(-c3cccc(F)c3)n2)C(=O)O1

Procedure:
The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 3-fluorophenylboronic acid. LC-MS Method 3, tR=1.215 min, m/z=749. 1H NMR (CDCl3) 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.58-3.67 (m, 1H), 4.30-4.40 (m, 1H), 7.30-7.65 (m, 10H), 7.80-7.90 (m, 2H), 8.90-8.95 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:31][CH:32]([CH3:34])[CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:18](=[O:29])[N:17]2[CH3:30])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[OH:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:19]2[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:31][CH:32]([CH3:33])[CH3:34])[C:4]([OH:35])=[O:3])=[CH:8][CH:9]=3)[N:17]([CH3:30])[C:18]2=[O:29])=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCC2CN(Cc3ccc(O)cc3)C(=O)N2C)cc1)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)OC(Cc1ccc(OCCC2CN(Cc3ccc(O)cc3)C(=O)N2C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A solution of 3-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionic acid ethyl ester (0.048 g, 0.089 mmol) in ethanol (8 mL) was treated with aqueous 5 N NaOH (1.5 mL) and stirred at room temperature for 2 h. The solvent removed in vacuo. The resultant residue was acidified with aqueous 1 N HCl (15 mL) and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 0.038 g (84%) 3-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-isopropoxy- propionic acid. 1H NMR (500 MHz, CDCl3) δ 7.49 (d, 2H, J=8.07 Hz), 7.30 (d, 2H, J=8.07 Hz), 7.06 (d, 2H, J=8.31 Hz), 6.66 (d, 2H, J=8.31 Hz), 4.40, 4.31 (ABq, 2H, J=15.65 Hz), 4.03-4.01 (m, 1H), 3.90 (t, 2H, J=5.87 Hz), 3.59-3.53 (m, 1H), 3.48 (hp, 1H, J=5.87 Hz), 3.31 (t, 1H, J=8.80 Hz), 3.12-2.96 (m, 1H), 2.95 (t, 1H, J=8.80 Hz), 2.90-2.79 (m, 1H), 2.78 (s, 3H), 2.27-2.23 (m, 1H), 1.93-1.84 (m, 1H), 1.14 (d, 3H, J=5.87 Hz), 0.97 (d, 3H, J=5.87 Hz). HRMS (ES+) m/z exact mass calc'd for C26H32N2O5F3 (M+1) 509.2274. Found m/z 509.2263.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.[C:19]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:46])[O:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][N:36]([CH3:45])[C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=O)[CH2:30][CH2:29]1>>[C:19]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26]([O:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][N:36]([CH3:45])[C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]3)[CH2:30][CH2:29]1)=[O:46]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Yield: 19.1 %

Procedure:
tert-Butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (227 mg, 0.914 mmol) and the compound (638 mg, 1.37 mmol) obtained in Example 4g were used to give the title compound (122 mg; yield, 19%) as a colorless oily substance according to the method described in Example 45b.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].Cl.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH2:29][NH:28][CH2:27]2)=[CH:22][CH:21]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:28]2[CH2:29][CH2:30][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH2:27]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: Clc1ccc([C@@H]2CNCC[C@@H]2c2ccccc2)cc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2ccc(Cl)cc2)C1

Procedure:
The title compound, MS: m/e=512.2 (M+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-3-(4-chloro-phenyl)-4-phenyl-piperidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:14][P:15]([O:20]CC)([O:17]CC)=[O:16])=[CH:7][C:8]([O:12]C)=[N:9]2)=[CH:4][CH:3]=1.[K+].[Br-]>C[Si](Br)(C)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:14][P:15]([OH:17])([OH:20])=[O:16])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1cc(OC)nc2cc(Cl)ccc12)OCC
Agent: C[Si](C)(C)Br
Agent: [Br-]
Agent: [K+]
Product: O=c1cc(CP(=O)(O)O)c2ccc(Cl)cc2[nH]1

Procedure:
A solution of diethylphosphonate 17 (160 mg; 0.57 mmol) in trimethylsilylbromide (4 ml) was refluxed overnight. The solvent/reagent was removed in vacuo and the residue was dissolved in 3 ml of 1N NaOH and washed with 2×1 ml of ether. The aqueous layer was acidified to pH 1 with 6N HCl and the precipitate which was formed was collected and washed with cold water, methanol and ether. The product was obtained as a white solid, mp 186° C. (dec) (80 mg; 60%). 1H NMR (D20): δ 3.06 (d, 2H, J=20.3 Hz); 6.54 (d, 1H, J=3.32 Hz); 7.12 (dd, 1H, J=2.03, 8.89 Hz); 7.36 (d, 1H, J=2.03 Hz); 7.89 (d, 1H, j=8.80 Hz). IR (KBr): 2931, 2828, 2360, 2309, 1658, 1643, 1532, 1406, 1224, 1147, 1093 cm-1. Anal. Calc' d for C10H9NO4ClP: C, 43.89; H, 3.32; N, 5.12. Found: C, 43.69; H, 3.41; N, 5.02.