Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C@@:8]2([CH2:23][OH:24])[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[C:1]1([C@@H:7]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH2:11][CH:10]3[C@@:8]2([C:23]([OH:27])=[O:24])[CH2:9]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N2CC3C[C@@]3(CO)[C@@H]2c2ccccc2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CC3C[C@@]3(C(=O)O)[C@@H]2c2ccccc2)cc1
Yield: 64 %

Procedure:
To a stirred solution of racemic Intermediate 16, one enantiomer being [(1S,2S)-2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-methanol I (34.5 g, 101 mmol) in acetone (1330 mL) was added Jones Reagent (104 mL) dropwise with stirring. The orange solution was stirred for another 20 minutes. MeOH (˜10 mL) was added cautiously until the solution turned green. The solvent was removed at reduced pressure and the residue partitioned between water and methylene chloride. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. This material was flash chromatographed on silica using a gradient of 10% to 80% EtOAc/Hexanes to give the title compound (23.0 g, 64% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[N:10]([CH:15]([CH3:17])[CH3:16])[C:11]([CH3:14])=[N:12][CH:13]=2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.C[O:19][C:20]([C:22]1[S:23][C:24](Br)=[CH:25][CH:26]=1)=[O:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O1CCOCC1.C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[C:3]([C:9]2[N:10]([CH:15]([CH3:17])[CH3:16])[C:11]([CH3:14])=[N:12][CH:13]=2)=[N:4][C:5]([NH:8][C:24]2[S:23][C:22]([C:20]([OH:21])=[O:19])=[CH:26][CH:25]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(Br)s1
Reactant: Cc1ncc(-c2nc(N)ncc2F)n1C(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1ncc(-c2nc(Nc3ccc(C(=O)O)s3)ncc2F)n1C(C)C
Temperature: 130 °C
Reaction time: 13 h

Procedure:
A mixture of the above amine (235 mg, 1.71 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (565 mg, 2.56 mmol), Pd2(dba)3 (31 mg, 0.03 mmol), XantPhos (49 mg, 0.09 mmol) and Cs2CO3 (1.1 g, 3.42 mmol) in dioxane was heated in a pressure vessel at 130° C. After 13 hours, the reaction mixture was diluted with dioxane/THF (1:1, 40 mL) and stirred. The mixture was then filtered through celite pad and washed with DCM/THF. The filtrate was then concentrated and used further without purification. MS found for C17H18FN5O2S as (M+H)+ 376.15. To the above crude ester in MeOH/THF (1:1) (10 mL) was added 3N NaOH (4.0 mL) and stirred at 55° C. After 16 hours, the reaction mixture was concentrated, diluted with water and washed with ether (3×). The aqueous phase was then neutralized with 6N HCl (1.5 mL) and the precipitated solid was dried to give 5-[5-fluoro-4-(3-isopropyl-2-methyl-3H-imidazol-4-yl)-pyrimidin-2-ylamino]-thiophene-2-carboxylic acid which was used for the next step without purification. MS found for C16H16FN5O2S as (M+H)+ 362.07.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]=3[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:20]=3[S:19][C:17]=2[N:18]=1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCCC3
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)c1

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine yields 2-chloro-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[Cl-].[CH3:11][SiH:12]([CH3:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[CH3:14][C:13]([Si:12]([CH3:17])([CH3:11])[O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6])([CH3:16])[CH3:15]
Reactant: C[SiH](C)C(C)(C)C
Reactant: OCCOCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOCCO
Reaction time: 0.75 h
Yield: 97.9 %

Procedure:
20 g of diethyleneglycol is added to 9.05 g of sodium hydride in 320 cm3 of tetrahydrofuran, the reaction medium is agitated for 45 minutes, 28.3 g of dimethylterbutylsilane chloride is added, agitation is carried out for 3 hours while leaving the temperature to return to ambient. Extraction is carried out with ether, followed by washing with an aqueous solution of sodium bicarbonate, with salt water, drying and evaporating the solvent. 40.25 g of expected product is obtained.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:16]>C(Cl)Cl>[N:14]([C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=[CH:12][N:11]=1)=[C:15]=[S:16]
Reactant: Nc1cc(Oc2ccccc2)ncn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: S=C=Nc1cc(Oc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 192.5 %

Procedure:
A mixture of 6-phenoxypyrimidin-4-amine (0.288 g, 1.538 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (0.357 g, 1.538 mmol) in DCM was stirred at rt for 18 h. The pale orange mixture was purified by silica gel chromatography (5-35% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-phenoxypyrimidine (0.55 g, 2.96 mmol, 85% yield) a yellow oil. LCMS R.T.=2.78; [M+H]+=229.94.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[N:37]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH:43]2[CH2:48][CH2:47][N:46]([C:13](=[O:14])[C@H:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:31][CH2:30][C:29]5[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=5[NH:27][C:26]4=[O:36])[CH2:21][CH2:20]3)=[O:18])[CH2:11][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg (1.01 mmol) [1,4′]bipiperidinyl.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[N:17]=2)=[CH:12][CH:11]=1.[C:33](=O)([O:36]C)[O:34][CH3:35]>>[CH3:35][O:34][C:33](=[O:36])[CH2:22][C:20]1[CH:19]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=2)[N:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH:21]=1
Reactant: Cc1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)Cc1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A solution of LDA (1.8 M in THF/heptane/ethyl benzene, 1.1 mL, 2.0 mmol) was added slowly to a stirred solution of 2-(4-fluoro-phenyl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (260 g, 0.8 mmol) under N2 at −78° C. After 30 minutes dimethyl carbonate (200 μL, 2.0 mmol) was added. After stirring at −78° C. for an additional 30 minutes, the solution was allowed to warm slowly and stirred at 0° C. for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl (2 mL). The mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2 (2×). The combined extracts were washed with brine, then dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (40-80% CH2Cl2 in heptane) to give the product as a white solid (130 mg, 42%). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=7.91 Hz, 2H), 8.13 (dd, J=5.46, 8.85 Hz, 2H), 7.75 (d, J=8.29 Hz, 2H), 7.64 (d, J=2.64 Hz, 2H), 7.19 (t, J=8.67 Hz, 2H), 3.78 (s, 2H), 3.76 (s, 3H). MS m/e 390.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[CH2:6][O:7][C:8]([C:10]1C(C2C=CC=C([N+]([O-])=O)C2=C=O)C(OCCOC)=C(C)[NH:14][C:15]=1[CH3:16])=[O:9]>C(O)C>[CH3:40][O:39][C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:36]=1[O:37][CH3:38])[CH2:6][O:7][C:8](=[O:9])/[CH:10]=[C:15](\[NH2:14])/[CH3:16]
Reactant: COCCOC1=C(C)NC(C)=C(C(=O)OCc2cc(OC)c(OC)c(OC)c2)C1C1C=CC=C([N+](=O)[O-])C1=C=O
Solvent: CCO
Product: COc1cc(COC(=O)/C=C(/C)N)cc(OC)c1OC
Yield: 71 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid 2-methoxyethyl ester and 75 mmols of β-aminocrotonic acid 3,4,5-trimethoxybenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-(2-methoxyethoxy)-carbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3,4,5-trimethoxybenzyl ester of melting point 160° C (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=S.C([O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[CH:17]=1)C.CS(Cl)(=O)=O>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]([OH:24])=[O:14])=[CH:17][C:18]=2[N:23]=1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reaction time: 48 h

Procedure:
A mixture of 1,3-dichloro-2-isothiocyanato-benzene (4.50 g, 22.1 mmol) in 50 mL dichloromethane was added to a stirred solution of 3,4-diamino-benzoic acid ethyl ester (4.00 g, 22.2 mmol) in 100 mL dichloromethane. After stirring for 2 days the mixture was concentrated i.vac. The residue was taken up in 200 mL dichloromethane. TEA (7.0 mL, 49.9 mmol) and DMAP (100 mg, 0.8 mmol) were added. A mixture of methanesulfonyl chloride (1.70 mL, 22.0 mmol) in 50 mL dichloromethane was added to the solution and stirred overnight. The mixture was concentrated i.vac. The residue was taken up in methanol and 4 M NaOH (aq) was added. After stirring overnight at ambient temperature the mixture was heated to reflux for 2 h and concentrated i.vac. The residue was taken up in water and methanol and neutralized with HCl (aq). The mixture was filtered and washed with water.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]=[CH:3][CH2:4][OH:5].[H-].[Na+].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>CN(C)C=O>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:5][CH2:4][CH:3]=[CH:2][CH2:1][O:6][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(CCl)cc1
Reactant: OCC=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCC=CCOCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 69.5 %

Procedure:
To a solution of 2-buten-1,4-diol (4.9 g, 60 mmol) in dry dimethylformamide (120 ml) was added sodium hydride (60% dispersion in oil; 5.28 g, 132 mmol) and the mixture was stirred at room temperature for 100 minutes. To this solution was added 4-methoxybenzyl chloride (17.9 ml, 132 mmol) in dimethylformamide (30 ml) dropwise over 45 minutes and the mixture was stirred for a further 40 minutes. The mixture was partitioned between ether (150 ml) and water (150 ml). The organic layer was further washed with water (150 ml), dried (magnesium sulphate) and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with hexane-acetone (4:1, 3:1) to afford 1,4-bis(4-methoxybenzyloxy)but-2-ene as a clear colourless liquid (13.7 g, 70%). IR: υmax (film) 2840, 1615, 1515 and 1250 cm-1. 1H NMR: δH (CDCl3) 3.80 (6H, s, 2×CH3), 4.02 (4H, d, J=4.5 Hz, 2×CHCH2), 4.43 (4H, s, 2×ArCH2), 5.79 (2H, t, J=4.5 Hz, 2×CH), 6.88 (4H, d, J=9 Hz, ArH) and 7.27 (4H, d, J=9 Hz, ArH).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[CH2:4](Br)[C:5]1[CH:13]=[CH:12][C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18]>[O-2].[Zn+2].ClC(Cl)C>[CH2:15]([O:19][CH2:4][C:5]1[CH:13]=[CH:12][C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=1)[C:16]#[C:17][CH3:18]
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: CC#CCO
Agent: [Ca+2]
Agent: [Cl-]
Agent: [O-2]
Solvent: CC(Cl)Cl
Product: CC#CCOCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask equipped with magnetic stirred condenser and drying tube filled with calcium chloride, 3.0 g, (13.95 mmol) of piperonyl bromide, 2.0 g (27.9 mmol) of 2-butyn-1-ol and 50 ml of dichloroethane are placed. After the addition of zinc(II) oxide (1.1 g, 13.5 mmol) the suspension is stirred at room temperature for 1 hour. The reaction is accompanied by a characteristic chance of colour. The mixture is then filtered, the filtrate is evaporated. The residual oil is dissolved in 50 ml of ether, washed within 2×10 ml of water, dried and evaporated. Yield 2.3 g (11.2 mmol, 80.7%), GC 82%. IR(CHCl3, cm−1) υ: 2997, 2946, 2921, 2888, 2376, 1609, 1503, 1491, 1445, 1251, 1099, 1070, 1042, 937, 865, 810; 1H-NMR (400 MHz, CDCl3) δ: 1.87 (3H, t, J=2.3 Hz, Me), 4.10 (2H, q, J=2.3 Hz, O—CH2—C≡), 4.47, (2H, s, O—CH2—Ar), 5.94 (2H, s, O—CH2—O), 6.76 (1H, d, J=8 Hz, H-7), 6.81 (1H, dd, J=8.15 Hz, H-6), 6.86 (1H, J=1.5 Hz, H-4); 13C-NMR (100 MHz, CDCl3) δ: 3.52 (Me), 57.29 (O—CH2—C≡), 71.15 (O—CH2—Ar), 82.54 (CH3—C≡), 100.9 C-2, 107.95, 108.71 (C-4, 7), 121.66 (C-6), 131.39, (C-5), 147.15, 147.66 (C3a, C-7a);
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(C(C)C)CC)(C)C.[Br:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>CN1C(=O)CCC1.O>[Br:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 66.5 %

Procedure:
To a mixture of 4-chloro-3-nitrobenzonitrile (A) (5 g, 27.4 mmol) and diisopropyl-ethylamine (4.24 g, 32 mmol) in NMP (40 mL) was added 3-bromoaniline (B) (4.71 g, 27.4 mmol) and the reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was cooled to RT and diluted with water. The solid was filtered off, washed several times with water to remove excess 3-bromoaniline, dried under vacuum to give compound C (5.8 g, 66%) as a pale yellow solid.
Reaction SMILES: C(OC(CC[NH:8][CH:9]=[C:10]([C:16](=[O:27])[C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[C:18]=1F)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:25][C:19]1[CH:18]=[C:17]2[C:22](=[C:21]([F:23])[C:20]=1[F:24])[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]2[OH:27]
Reactant: CCOC(=O)CCNC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(F)c(F)c(F)cc2c1O

Procedure:
7.7 g of the compound from Example 6 and 2.9 g of K2CO3 are heated at 140°-5° C. for 4 hours in 36 ml of DMF. The mixture is subsequently poured onto ice and acidified, and the precipitated solid is separated off and dried.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:27])[C:25]=1[OH:26])[CH:21]=O>C(O)C.Cl.C(O)(C)C.O>[OH:26][C:25]1[C:24]([CH3:27])=[CH:23][C:20]([CH2:21][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=2)=[O:10])=[CH:19][C:18]=1[CH3:17]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CCc1sc(C(C)=O)cc1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Reaction time: 1.5 h
Yield: 58.2 %

Procedure:
A solution of 1-(5-ethyl-4-phenyl-thiophen-2-yl)-ethanone (64 mg, 0.278 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (53 mg, 0.334 mmol) in ethanol (1.2 mL) and 5 N HCl in isopropanol (0.6 mL) is stirred at rt for 1 h. The dark green solution is diluted with water and extracted with EA. The organic extract is evaporated, dissolved in methanol (1 mL) and THF (1 mL), and treated with Pd/C (60 mg, 10% Pd). The slurry is hydrogenated under 1.4 bar of H2 for 1.5 h. The mixture is filtered over celite, the solvent is removed in vacuo and the crude product is purified on prep. TLC plates with heptane:EA 2:1 to give 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (59 mg) as a yellow oil; LC-MS: tR=1.11 min; 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.46-7.30 (m, 5H), 6.85 (s, 2H), 4.56 (s, 1H), 3.18-3.10 (m, 2H), 2.97-2.86 (m, 4H), 2.22 (s, 6H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]O)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]1([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][O:17][C:16]([C@@H:11]3[CH2:12][S:13][CH2:14][CH2:15][N:10]3[S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=3)(=[O:9])=[O:8])=[O:18])=[CH:32][CH:33]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 103.4 %

Procedure:
0.200 g (0.6 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.184 g (1.0 mmol) of 4-phenylbenzyl alcohol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:9) to obtain the product as a oil (0.29 g).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(Cc4ccccc4)CC3)cc2)nc1
Reaction time: 15 h
Yield: 56.7 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (from step 1 above) (0.300 g, 1.24 mmol) and 1-benzylpiperazine (0.35 mL, 2.01 mmol) in methanol (12 mL) and stir at ambient temperature. After 15 h, add sodium borohydride (0.108 g, 2.85 mmol) and stir. After 1 h, filter the white precipitate and dry under vacuum to give 0.283 g (57%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C24H17N4O2 403.2134, found 403.2128: 1H NMR (DMSO-d6): 8.63 (d, 1H, J=1.5 Hz), 8.27 (dd, 1H, J=2.4, 8.3 Hz), 8.05 (s br, 1H), 7.50 (s br, 1H), 7.39-7.23 (m, 7H), 7.15-7.06 (m, 3H), 3.48 (m, 4H), 2.41 (s br, 8H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[N:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]2=[CH:13][C:12]=1[C:20](O)=[O:21].[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH2:31])[CH2:26][O:25]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH:31][C:20]([C:12]2[CH:13]=[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]3[C:11]=2[NH:10][C:3]2[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:26][O:25]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: CSc1ccc(Nc2c(C(=O)O)cc3ccncn23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ccc(Nc2c(C(=O)NOC[C@H]3COC(C)(C)O3)cc3ccncn23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
7-(2-Fluoro-4-methylsulfanyl-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid (287 mg, 0.90 mmol), O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (133 mg, 0.90 mmol), HOBt (135 mg, 0.99 mmol), EDCI hydrochloride (191 mg, 0.99 mmol) and DIPEA (169 μL, 0.99 mmol) were dissolved in DMF (5 mL). The reaction was stirred at room temperature for 1 hour then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 30-100% ethylacetate in cyclohexane) to yield the title compound as a brown solid (246 mg, 61%). LCMS (Method B): RT=3.28 min, M+H+=447.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:7]=1.[NH2:29][CH2:30][C@H:31]([OH:34])[CH2:32][OH:33]>>[OH:34][C@H:31]([CH2:32][OH:33])[CH2:30][NH:29][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[C:25]([F:27])([F:28])[F:26])=[N:14][C:15]=12)=[O:24]
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Reactant: NC[C@H](O)CO
Product: O=C(NC[C@H](O)CO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Yield: 73 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation M) and (S)-3-aminopropane-1,2-diol. The crude material was purified by reverse phase HPLC (0-60% acetonitrile/water) to provide the title compound (26 mg, 73% yield). MS (apci) m/z=468.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[C:7](=O)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[CH:3]=1.O.NN.[OH-].[K+]>C(O)COCCO.O>[CH3:1][C:2]1[S:6][C:5]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)C(=O)c1ccccc1-2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Cc1cc2c(s1)Cc1ccccc1-2
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A mixture of 6.83 g (0.034 mol) of 2-methyl-8H-indeno[2,1-b]thiophen-8-one and 9.1 mL (0.182 mol) of hydrazine monohydrate in 91 mL of diethylene glycol was stirred at 80° C. for 40 min and then refluxed for 1 h. The resulting mixture was cooled to room temperature, treated with a solution of 9.5 g (0.169 mol) of KOH in 34 mL water and then refluxed for 2 h. The resulting mixture was poured into 600 mL of water, the precipitate was filtered, washed 5 times with 200 mL of water and dried. Yield 5.8 g (92%).