Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:15]([CH3:16])[NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18](=[O:21])(=[O:20])=[O:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:30][N:31]([CH3:34])[CH:32]=O>>[CH2:30]([N+:31]([CH2:34][CH2:13][CH2:12][CH3:15])([CH2:16][CH2:15][CH2:12][CH3:13])[CH2:32][CH2:4][CH2:5][CH3:6])[CH2:1][CH2:2][CH3:3].[CH3:16][C@@H:15]1[N:14]([S:18]([O-:21])(=[O:20])=[O:19])[C:13](=[O:17])[C@H:12]1[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CN(C)C=O
Reactant: O=S(=O)=O
Reactant: C[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCCC[N+](CCCC)(CCCC)CCCC
Product: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 600 mg of (3S-trans)-3-benzyloxycarbonylamino-4-methylazetidinone in 2 ml of dimethylformamide was cooled to 0° C. and 4 ml of 0.8M sulfur trioxide in dimethylformamide was added. The solution was stirred at room temperature under nitrogen for 1 hour and poured into 80 ml of cold 0.5M monobasic potassium phosphate (adjusted to pH 5.5). The solution was extracted with three 50 ml portions of methylene chloride (discarded) and 868 mg of tetrabutylammonium bisulfate was added. The resulting solution was extracted with four 75 ml portions of methylene chloride. The combined organic layer was washed with 8% aqueous sodium chloride, dried, and evaporated in vacuo yielding 1.54 g of the title compound.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[C:24]([OH:26])[C:23]([C:27]([OH:29])=[O:28])=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[O:12])[CH3:10])=O)(C)(C)C.N1C=CC=[CH:32][CH:31]=1.C(OC(=O)CC)(=O)CC>CO>[C:6]([NH:8][C@H:9]([C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:25]=[C:24]([OH:26])[C:23]([C:27]([OH:29])=[O:28])=[CH:22][N:21]=2)=[CH:18][CH:19]=1)=[O:12])[CH3:10])(=[O:5])[CH2:31][CH3:32]
Reactant: c1ccncc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Agent: CCC(=O)OC(=O)CC
Solvent: CO
Product: CCC(=O)N[C@@H](C)C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: 25 °C

Procedure:
A suspension of 1.90 g (6.3 mmol) of the above pyrimidine acid and 20 ml of pyridine is stirred at room temperature and 5 ml of propionic anhydride is added. After stirring 1 hr at room temperature, methanol (10 ml) is added and the mixture evaporated to a syrup in vacuo. Water is added to the residue, the pH is adjusted to 2.3 with dilute HCl, and the product filtered. After washing with water and drying gives 1.93 g of 2-[4-(N-propionyl-L-alanylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid; mp 247°-248° C. [α]D25 -81° (cl, pH 7).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16][C:17]1[S:26][C:20]2[N:21]=[C:22](Cl)[N:23]=[CH:24][C:19]=2[C:18]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[Br:16][C:17]1[S:26][C:20]2[N:21]=[C:22]([N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:11][CH2:12]3)[N:23]=[CH:24][C:19]=2[C:18]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Clc1ncc2c(-c3ccccc3)c(Br)sc2n1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Brc1sc2nc(N3CCC(COCCN4CCCC4)CC3)ncc2c1-c1ccccc1
Yield: 42.9 %

Procedure:
4-(2-Pyrrolidin-1-ylethoxymethyl)piperidine (0.567 g, 1.74 mmol), 6-bromo-2-chloro-5-phenyl-thieno[2,3-d]pyrimidine (0.554 g, 2.61 mmol) and potassium carbonate (7.21 g, 7.7 mmol) were combined and heated in acetonitrile for 30 minutes to 150° C. in the microwave. The reaction mixture was diluted with DCM, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with DCM—92/8/2 DCM/MeOH/NH4OH gradient to afford 6-bromo-5-phenyl-2-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine (374 mg). LCMS [M+H]+=501.1
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](C=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)O[C:18](C)=O.[Na+].CC(O)=O>ClC(Cl)C>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc(N2CCOCC2)nc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 6-bromo-2-pyridine-carboxaldehyde (200 mg, 1.08 mmol) in dichloroethane (10 mL) was added morpholine (0.14 mL, 1.62 mmol) followed by NaBH(OAc)3 (458 mg, 2.16 mmol) and AcOH (0.25 mL, 4.32 mmol). The resulting mixture was stirred at RT for 12 h. The reaction was quenched with 2M Na2CO3 solution and stirred 1 h. The mixture was poured into Et2O and washed with 2 M Na2CO3 solution. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo to give 2-bromo-6-morpholinyl-methylpyridine as a white solid. MS m/z: 256.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]=[C:8]([C:10]#[N:11])[S:9][C:5]=2[CH:4]=1.C[O-].[Na+].[Cl-:17].[NH4+:18]>>[ClH:17].[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]=[C:8]([C:10](=[NH:18])[NH2:11])[S:9][C:5]=2[CH:4]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COc1ccc2nc(C#N)sc2c1
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc2nc(C(=N)N)sc2c1
Product: Cl
Yield: 74.9 %

Procedure:
6-methoxybenzo[d]thiazole-2-carbonitrile (1 g, 5.26 mmol) was reacted with sodium methoxide (0.28 g, 5.26 mmol) and ammonium chloride (0.6 g, 11 mmol) according to the procedure as described in Example 61, Step B to give the title compound as a white solid (0.96 g, 75%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[N:14]1([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26]([CH:31]=O)=[CH:25]3)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[O:1]=[C:2]1[C:10](=[CH:31][C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([O:21][CH2:20][CH2:19][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:30][CH:29]=3)[C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2cc(C(=O)O)ccc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-6-carboxylic acid was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.CC(OC(/N=N/C(O[CH:27]([CH3:29])[CH3:28])=O)=O)C.[Cl:30][C:31]1[CH2:36][C:35]([Cl:40])(OCC)C=[CH:33][C:32]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:40][C:35]1[CH:36]=[C:31]([Cl:30])[CH:32]=[CH:33][C:29]=1[CH2:27][CH2:28][O:1][C:2]1[CH:3]=[C:4]([S:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)Sc1cccc(O)c1
Reactant: CCOC1(Cl)C=CC(O)=C(Cl)C1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Sc1cccc(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
The title product was prepared according to the procedure described in Method B starting from methyl 2-(3-hydroxyphenylthio)iso-butyrate (prepared as described in example 1) (0.280 g, 1.24 mmol) and DIAD (0.325 g, 1.61 mmol) dissolved in 3 mL of anhydrous THF and added dropwise to a solution of 2,4-dichlorophenetylalcohol (0.260 g, 1.36 mmol), and triphenylphosphine (0.422 g, 1.61 mmol) in 4 mL of anhydrous THF at 0° C. The reaction was left overnight under magnetic stirring at room temperature. After this period, the solvent was evaporated and the residue purified by silica gel chromatography using hexane/AcOEt 9.6/0.4 as eluent. 0.327 g of oily product were obtained (yield: 66%); TLC: silica gel, eluent hexane/AcOEt 9/1, Fr: 0.34; 1H NMR (CDCl3, 300 MHz) δ: 7.40 (d, 1H), 7.20 (m, 3H), 7.00 (m, 2H), 6.90 (dd, 1H), 4.15 (t, 2H), 3.65 (s, 3H), 3.20 (t, 2H), 1.45 (s, 6H); HPLC: Column: Inertisil ODS—3 (5 μm) 4.6×250 mm, T: room temperature, mobile phase CH3CN/H2O 90/10 (v/v), pH: as is, flow rate: 0.8 mL/min, 205 nm UV detector, retention time 12.40 min; KF: 0.2% H2O; E.A. conforming for C19H20Cl2O3S.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][CH3:28])=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].O>C(Cl)Cl>[CH3:28][NH:27][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][NH:1][C:36](=[O:38])[CH3:37])=[CH:10][CH:9]=3)[CH:12]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OCCN)cc3)cc12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OCCNC(C)=O)cc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
In a 50 mL round-bottomed flask was added 6-(4-(2-aminoethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (15.0 mg, 0.040 mmol) and triethylamine (0.017 ml, 0.121 mmol) in CH2Cl2 (5 mL) to give a yellow solution. Acetic anhydride (4.58 μl, 0.048 mmol) was added and the mixture was stirred for 2 h at room temperature. Water (10 mL) was added to the mixture and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL), dried over Mg2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with CH2Cl2/MeOH 1:0 to 9:1). The product was converted to the HCl salt by addition of 4 M HCl-dioxane, then dissolved in a small amount of methanol, followed by ethyl acetate. The resulting solid was filtered and dried to give 10 mg of N-(2-(4-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenoxy)ethyl)acetamide as a HCl salt as a yellow solid in a 51% yield. LCMS m/z=414 (M+1) (Method C) (retention time=1.28 min). 1H NMR (300 MHz, DMSO) δ 10.26 (s, 1H), 9.62 (s, 1H), 9.06-8.90 (m, 2H), 8.81 (s, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.17 (d, J=6.6 Hz, 2H), 7.86 (d, J=8.0 Hz, 3H), 7.13 (d, J=7.91 Hz, 2H), 4.06 (t, J=5.4 Hz, 2H), 3.52-3.38 (m, 2H), 3.30 (d, J=4.1 Hz, 3H), 1.84 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[NH:11]1[CH2:19][CH2:18][CH:14]([C:15](O)=O)[CH2:13][CH2:12]1.[OH-].[Na+]>>[Br:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]2[O:10][C:15]([CH:14]3[CH2:18][CH2:19][NH:11][CH2:12][CH2:13]3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)cc(F)c1O
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: Fc1cc(Br)cc2nc(C3CCNCC3)oc12
Temperature: 195 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
2-amino-4-bromo-6-fluorophenol (1.7 g, 8.24 mmol) and isonipecotic acid (1.06 g, 8.24 mmol) were dissolved in polyphosphoric acid (28 g). This mixture was heated to 195° C. for 3 h. After 3 h, reaction mixture cooled to rt and basified with aqueous NaOH solution to pH 14. Solid that obtained was filtered and dried to obtain the title compound (1.3 g) as a brown solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CC([O-])(C)C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>O1CCOCC1>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Brc1ccccn1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccn2)CC1
Temperature: 90 °C

Procedure:
A mixture of 4-Amino-1-Boc-piperidine (2.0 g, 9.7 mmol), 2-Bromo-pyridine (1.93 mL, 19.4 mmol), NaOtBu (2.7 g, 27.1 mmol), 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (472 mg, 1.16 mmol) and Tris(dibenzylideneacetone)dipalladium Chloroforme Complex (620 mg, 0.58 mmol) in dioxane (10 mL) is heated to 90° C. After completion, the reaction mixture is quenched by H2O, DCM is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a white powder; ES-MS: M+H=278.3: AtRet=4.75.
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[ClH:15].[CH2:1]([N:8]([CH2:9][CH2:10][Cl:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(CCCl)Cc1ccccc1
Product: Cl
Temperature: 0 °C

Procedure:
N-Benzyl-N-methylethanolamine (200 ml) was dissolved in chloroform (600 ml). The solution was cooled to 0° C. with stirring and then thionyl chloride (100 ml) was added dropwise, with stirring, at a rate such that the temperature of the reaction mixture was kept below 15° C. The mixture was boiled under reflux for 2 hours and then evaporated to dryness. The solid residue was triturated with ether, filtered and dried to give N-benzyl-2-chloro-N-methylethylamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[CH:11](=O)[CH:12]([CH3:14])[CH3:13].CO>C(O)=O>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[N:4]=[CH:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C=O
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: O=CO
Solvent: CO
Product: Cc1cc(C)c(N=CC(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,4,6-Trimethylaniline (7.0 mL, 50 mmol, Aldrich) was mixed with isobutyraldehyde (4.5 mL, 50 mmol, Aldrich), methanol (20 mL), and formic acid (1 mL of a 88% aqueous solution, Fisher). The reaction mixture became reddish and was stirred at RT for 4 h. Assay by 1H-NMR showed a 2/1 mixture of product/starting materials. Additional isobutyric aldehyde (4 mL, 44 mmol) was added to the reaction mixture and it was stirred for 12 h. At this point assay by 1H-NMR showed a 5/1 mixture of product/amine. The solvent and excess aldehyde was evaporated, the residue was distilled at reduced pressure collecting three fractions: 1. 53–56° C./27 Pa, 1/1 mixture of product/amine; 2. 56–59° C., 7/1 product/amine; 3. 59–60° C., pure product (2.3 g, 24.3%). 1H NMR (CDCl3) 7.52 (d, 1H; J=4.8 Hz); 6.84 (br s, 2H); 2.70 (d of septets, 1H; J=4.8; 6.9 Hz); 2.26 (s, 3H); 2.05 (s, 6H); 1.22 (d, 6H; J=6.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]=[CH2:10])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[ClH:19]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][Cl:19])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cl
Reactant: C=CC(O)c1ccc(F)c(Oc2ccccc2)c1
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(/C=C/CCl)cc1Oc1ccccc1
Reaction time: 2 h

Procedure:
1-(4-Fluoro-3-phenoxyphenyl)prop-2-en-1-ol (38 g) was dissolved in tetrahydrofuran (400 cm3) and concentrated hydrochloric acid (180 cm3) was added with vigorous stirring. Stirring was continued for a further 2 hours, after which time, analysis of a withdrawn sample by gas liquid chromatography showed no starting material remaining. The mixture was diluted with water and the products extracted into ethyl acetate. The combined organic layers were washed with water (4 times), then dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave E-3-(4-fluoro-3-phenoxyphenyl)-1-chloroprop-2-ene (44 g) as a viscous oil, 98% pure by gas liquid chromatographic analysis.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]4[CH2:55][CH2:54][CH2:53][C@@H:52]4[C:56]([O:58][CH3:59])=[O:57])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:60][C:61]1[CH:69]=[CH:68][C:64]([C:65](Cl)=[O:66])=[CH:63][CH:62]=1>>[Cl:60][C:61]1[CH:69]=[CH:68][C:64]([C:65]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C@@H:51]5[CH2:55][CH2:54][CH2:53][C@@H:52]5[C:56]([O:58][CH3:59])=[O:57])[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:66])=[CH:63][CH:62]=1
Reactant: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4)cc3)cc2C1=O
Yield: 95 %

Procedure:
The compound of example 595 was prepared analogous to compound of example 97 by reaction of compound of example 592 with 4-chloro benzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[ClH:26].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([O:25][CH2:24][C:21]2[CH:20]=[CH:19][C:18]([S:15]([C:4]3[C:3]([O:2][CH3:1])=[CH:14][C:7]4[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=4[CH:5]=3)(=[O:17])=[O:16])=[CH:23][CH:22]=2)=[CH:29][CH:28]=1
Reactant: COc1cc2c(cc1S(=O)(=O)c1ccc(CO)cc1)CCN(C)CC2
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2c(cc1S(=O)(=O)c1ccc(COc3ccc(Cl)cc3)cc1)CCN(C)CC2
Product: Cl
Reaction time: 18 h

Procedure:
A solution of [4-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1-H-3-benzazepine-7-sulfonyl)-phenyl]-methanol D12 (0.12 g), 4-chlorophenol (0.042 g), triphenyl phosphine (0.087 g in tetrahydrofuran (5 mL) was treated with diisopropyl azodicarboxylate (0.066 g). The solution was stirred for 18 hour then the solvent was evaporated and the residue was purified by column chromatography on silica using 0-10% methanol (containing 0.5% aqueous ammonia)-dichloromethane to give the title compound E107, which was converted to the hydrochloride salt. 1H NMR: δ CDCl3 2.36 (3H, s), 2.55 (4H, m), 2.94 (4H, m), 3.73 (3H, s), 5.08 (2H, s) 6.64 (1H, s), 6.87 (2H, d), 7.22 (2H, d), 7.50 (2H, d) 7.84 (1H, s) 7.98 (2H, d). Mass Spectrum MH+ 472
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]1([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1>>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([C:19]2([NH:18][C:14]([C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:20][CH2:21]2)=[CH:23][CH:24]=1)=[O:27]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 78.2 %

Procedure:
The title compound (D53) (650 mg) was prepared according to the general procedure for amides preparation (Method A) starting from (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (500 mg, available from Sigma Aldrich #516341), and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (470 mg). Reaction time: 18 hrs.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[O:25]C(C)(C)[N:23]([C:28](=[O:32])[CH:29]([F:31])[F:30])[C@@H:22]3[CH2:33][F:34])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:7][CH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([OH:25])[C@H:22]([NH:23][C:28](=[O:32])[CH:29]([F:30])[F:31])[CH2:33][F:34])=[CH:17][CH:16]=2)=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ncc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ncc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (5-{4-[(4S,5R)-3-(2,2-Difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyrimidin-2-ylmethyl)-carbamic acid tert-butyl ester (0.125 g, 0.253 mmol) in CH2Cl2 (10 mL) is added trifluoroacetic acid (1.0 mL) at room temperature. Resulting reaction mixture is allowed to stir at room temperature for 5 hours. The solvent evaporated in vacuo and the crude material is striped out with CH2Cl2 followed by washing with diethyl ether and dried in lipholiser to afford title compound (0.1 g): 1H NMR (400 MHz, DMSO-d6) δ: 4.31-4.33 (m, 1.5H), 4.36 (d, J=8.84 Hz, 2H), 4.42-4.46 (m, 0.5H), 4.56-4.57 (m, 0.5H), 4.66-4.70 (m, 0.5H), 4.92 (t, J=3.76 Hz, 1H), 5.98 (d, J=4.6 Hz, 1H), 6.20 (t, J=53.72 Hz, 1H), 7.52 (d, J=8.24 Hz, 2H), 7.84 (d, J=8.24 Hz, 2H), 8.36 (bs, 2H), 7.86 (d, J=8.84 Hz, 1H), 9.24 (s, 2H). LC-MS (m/z): [M+H]=354.9.
Reaction SMILES: Cl[P:2]([CH3:4])[CH3:3].[O-:5]CC.[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1>C1COCC1>[CH3:3][P:2](=[O:5])([CH3:4])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CP(C)Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CP(C)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
A solution of chlorodimethylphosphine (250 mg, 2.60 mmol) in THF (0.7 mL) was added dropwise to a stirred suspension of sodium ethoxide (194 mg, 2.85 mmol) in THF (0.8 mL) at 0° C. The resulting mixture was stirred at room temperature for 30 min. then treated with 1-(bromomethyl)-3-nitrobenzene (560 mg, 2.59 mmol). The mixture was then stirred under nitrogen at 100° C. in a sealed tube for 2 h., concentrated in vacuo and the residue purified by chromatography over silica gel eluting with 5% MeOH in dichloromethane to afford 153 mg of dimethyl(3-nitrobenzyl)phosphane oxide (yield: 28%). 1H-NMR (CDCl3, 400 MHz): δ=1.53 (d, J=12.4 Hz, 6 H), 3.27 (d, J=14.0 Hz, 2 H), 7.55 (t, J=7.6 Hz, 1 H), 7.71 (d, J=7.6 Hz, 1 H), 8.11 (d, J=2.0 Hz, 1 H), 8.16 (dd, J=0.8, 7.2 Hz, 1 H). MS (ES+): m/z 214.00 (MH+). HPLC: tR=2.16 min (ZQ3, polar—5 min).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH:12]1[C:16](C)([C:17]([O:19]CC)=O)[CH:15]=[CH:14][S:13]1.[CH:23](Cl)(Cl)Cl>>[CH3:23][C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:19])[C:16]=2[CH:15]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)C1(C)C=CSC1N
Product: Cc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Temperature: 185 °C
Reaction time: 6 h

Procedure:
A mixture of 6.0 g (0.038 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 10.0 g (0.054 mol) of 2-amino-3-methyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) is heated in an oil bath at 185° C. for one hour then at 135°-140° C. for sixteen hours and finally at 195° C. for six hours. The mixture is cooled and then suspended in hot chloroform and filtered to give 0.6 g of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 350°-354° C. after recrystallization from pyridine.