Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:18][C@@H:2]1[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>CCOC(C)=O.CC(O)C>[CH:8]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[C:5]([O:4][CH2:3][C@H:2]([OH:1])[CH2:18][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@H]3CO3)c12
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC[C@@H](O)COc2cccc3[nH]c4ccccc4c23)c(OC)c1
Temperature: 85 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
To a solution of (R)-(−)-4-(2,3-Epoxypropoxy)-carbazole (7 g, 0.029 mole) in EtOAc/IPA (40/80 mL) was added 2,4-dimethoxybenzylamine (8.7 mL, 0.058 mole) and the reaction mixture was slowly heated to 80-90° C. and then refluxed for 5 hours. Subsequently the reaction mixture was concentrated to half its volume, and cooled to room temperature to give a colorless solid. The solid was filtered, re-dissolved in EtOAc (60 mL) by refluxing, concentrated to 40 mL and the colorless precipitate formed on cooling to room temperature, was filtered and dried. Recrystallization of the residue obtained from the filtrate was repeated until maximum amount of the solid was recovered. The combined solid was triturated with diethylether by stirring for 6 hours, followed by filtration to afford 5.5 g (46% yield) of the desired compound as a colorless solid with m.p: 152-153° C. 1H NMR (400 MHz, CDCl3): δ 2.17 (s 1H), 2.86-2.92 (m, 1H), 2.99-3.02 (m, 1H), 3.74-3.86 (m, 8H), 4.18-4.32 (m, 3H), 6.38-6.44 (m, 2H), 6.67 (d, 1H, J=8.0 Hz), 7.04 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 7.18-7.41 (m, 4H), 8.09 (s, 1H), 8.21 (d, 1H, J=8.0 Hz). MS m/z: 407.1 (M+1). Chiral purity: 99.99%
Reaction SMILES: [Cl-].[C:2]([CH2:5][O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH3+:13])([OH:4])=[O:3].[C:14](OC(=O)C)(=[O:16])[CH3:15]>[OH-].[Na+]>[C:14]([NH:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[O:6][CH2:5][C:2]([OH:4])=[O:3])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: [NH3+][C@@H]1CCCC[C@H]1OCC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N[C@@H]1CCCC[C@H]1OCC(=O)O
Reaction time: 0.5 h
Yield: 278.8 %

Procedure:
To a cooled solution of trans-2-carboxymethoxy-cyclohexyl ammonium chloride (1.048 g, 5 mmoles) in 2N NaOH (5 ml), there were added under stirring first 1N NaOH (1 ml) and then acetic anhydride (0.102 g, 1 mmol). When the reaction of anhydride was completed and a homogeneous solution was obtained, the same amount of 1N NaOH and acetic anhydride as above was added four times. After the addition of the last portion the reaction mixture was stirred for 30 minutes, the solution was acidified to pH 2 and extracted with ethyl acetate (5×20 ml). The organic extracts were dried with MgSO4, the drying agent was filtered off and the filtrate was evaporated under reduced pressure. The residue was recrystallized from a mixture of chloroform/n-hexane. Thus, there were obtained 0.60 g (56%) of the title compound, melting point 141°-143° C.
Reaction SMILES: I[CH2:2][C:3]1([CH2:6][C:7]#[C:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.[CH2:13]([O:15][C:16](=[O:29])[C:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[CH3:28])([CH3:19])[CH3:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:29])[C:17]([CH3:19])([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]2([CH2:6][C:7]#[C:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]2)=[CH:23][C:22]=1[CH3:28])[CH3:18])[CH3:14]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: C[Si](C)(C)C#CCC1(CI)CC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC2(CC#C[Si](C)(C)C)CC2)cc1C

Procedure:
In analogy to the procedure described in example 20A], [3-(1-iodomethyl-cyclopropyl)-prop-1-ynyl]-trimethylsilane and 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) gave after 18 h at room temperature the title compound as light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:34])([CH:31]([F:33])[F:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[N:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[C:26](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:34])[CH:31]([F:32])[F:33])=[CH:24][CH:23]=2)[CH:29]=[N:28]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccc(OCC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 71.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.0 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.16 g of 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (1.34 g) was obtained as a colorless oil. IR ν cm-1 (film): 1716, 1705, 1616, 1558, 1516, 1257, 1108.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:23])=[O:22]
Reactant: COC(=O)c1cc(N)ccc1F
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Product: COC(=O)c1cc(NS(=O)(=O)c2c(F)cccc2F)ccc1F
Yield: 100 %

Procedure:
Following a procedure analogous to the procedure described in Example 5, Step A using methyl 5-amino-2-fluorobenzoate (10 g, 59.2 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (13.2 g, 62.2 mmol) the title compound of Step B was obtained (21 g, 100% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.58-7.60 (m, 1H), 7.38-7.48 (m, 2H), 7.10-7.15 (br, 1H), 6.89-6.97 (m, 2H), 6.97-7.06 (m, 1H), 3.85 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27].CN(C)C=O.C(Cl)(=O)C([Cl:40])=O>ClCCl>[O:1]=[C:2]1[C:10]2([C:11]3=[CH:21][C:20]4[CH2:19][CH2:18][O:17][C:16]=4[CH:15]=[C:12]3[O:13][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([Cl:40])=[O:27]
Reactant: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.13 g, 5.1 mmol) and N,N-dimethylformamide (0.001 mL, catalytic amount) in anhydrous dichloromethane (30 mL) was treated with oxalyl chloride (4.50 mL, 5.1 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The crude product was concentrated in vacuo to afford 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride as a light yellow solid. A solution of 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.27 g, 0.6 mmol), cyclohexanemethylamine (0.17 mL, 1.3 mmol), triethylamine (0.44 mL, 3.2 mmol), and 4-(dimethylamino)pyridine (0.005 g, catalytic amount) in anhydrous dichloromethane (5 mL), was stirred at ambient temperature for 20 h under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL) and aqueous citric acid (10 mL) and the phases were separated. The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0% to 100% gradient) to afford N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.33 g, 65%) as a colourless solid: 1H NMR (300 MHz, CDCl3) δ7.80 (s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.48-7.37 (m, 2H), 7.23-7.15 (m, 2H), 7.08-7.00 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 6.19-6.09 (m, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H), 3.33-3.23 (m, 2H), 3.07-2.95 (m, 2H), 1.82-1.64 (m, 5H), 1.34-1.13 (m, 4H), 1.07-0.86 (m, 2H); MS (ES+) m/z 509.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][NH:24][C:25](=O)[C:26]([CH3:29])([CH3:28])[CH3:27])=O)[C:9]=2[S:31][CH3:32])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1COCC1>[C:26]([C:25]1[S:42][C:21]([C:10]2[C:9]([S:31][CH3:32])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=2)=[N:23][N:24]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CSc1c(C(=O)NNC(=O)C(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CSc1c(-c2nnc(C(C)(C)C)s2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 77.9 %

Procedure:
To a solution of hydrazide (9) (70 mg, 0.136 mmol) and Lawesson's reagent (137 mg, 0.339 mmol) in THF (5 mL) was irradiated in a microwave reactor (Biotage Initiator™) for 50 minutes at 155° C. The organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (eluent: hexane/EtOAc=4/1) to obtain 54 mg (78%) of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(C)c3c([N+](=O)[O-])cccc32)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A suspension of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (54 mg, 0.19 mmol) in absolute EtOH (1.5 mL) was treated at ambient temperature with 10% palladium hydroxide on carbon (27 mg, 0.019 mmol). The mixture was stirred at ambient temperature under a hydrogen atmosphere for 16 hours, and then filtered through a Celite pad, washing with EtOH. The filtrate was concentrated under reduced pressure to afford the product (36 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[H-].[Na+].Cl[C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[N:25]=1.O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[N:25]=1)[CH3:2]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Cl)nc(-n2ccnc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cc(C)nc(-n2ccnc2)n1
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
To a solution of (benzhydrylidene-amino)-acetic acid ethyl ester (2.67 g, 10.0 mmol) in DMSO (50 mL) was added NaH (600 mg of a 60% dispersion on mineral oil, 15.0 mmol) slowly at r.t. under nitrogen and the mixture was stirred for 5 min. Then a solution of 4-chloro-2-imidazol-1-yl-6-methyl-pyrimidine (1.95 g, 10.0 mmol) in DMSO (15 mL) was added and the reaction mixture stirred at r.t overnight. Water was added and the solution was extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent gave residue which was purified by column chromatography to give 1.30 g (31%) of (benzhydrylidene-amino)-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-acetic acid ethyl ester. [M+H]+ 426.18.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].[F:23][C:24]([F:35])([F:34])[C:25]1[N:29]2[CH2:30][CH2:31][NH:32][CH2:33][C:28]2=[N:27][N:26]=1>>[CH3:22][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([N:32]1[CH2:31][CH2:30][N:29]2[C:25]([C:24]([F:35])([F:23])[F:34])=[N:26][N:27]=[C:28]2[CH2:33]1)=[O:12])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Reactant: FC(F)(F)c1nnc2n1CCNC2
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)ccc1F
Yield: 48.7 %

Procedure:
The title compound was prepared from (3R)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 50 mg, 0.16 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (30 mg, 0.16 mmol) using a procedure analogous to that described for Example 1, Step C. The crude product was purified by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol/dichloromethane (2×)) to afford the title compound (38.1 mg) as a solid. 1H NMR (500 MHz, CDCl3) δ 1.38 (s, 9H), 2.57˜3.05 (m, 4H), 3.85˜4.30 (m, 5H), 4.90 (s, 1H), 4.95˜5.15 (m, 1H), 5.22˜5.40 (br, 1H), 6.86˜7.24 (m, 3H). LC/MS (M+1-t-Boc) 390.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][CH2:29][NH:30]3)=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:33].N1C=CC=CC=1>ClCCl>[CH3:12][O:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:32]=[C:31]3[C:27]([CH2:28][CH2:29][N:30]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1[Cl:33]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1Cl
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Chlorobenzenesulphonyl chloride (71 mg, 0.3 mmol, 1.1 equiv.) was added to a mixture of crude 2-chloro-4-[(2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester (100 mg, 0.3 mmol, 1 equiv.) and pyridine (0.2 mL, 2.4 mmol, 8 equiv.) in dichloromethane (2 ml) and the mixture was stirred at room temperature for 16 hours. The solvent was removed under a stream of N2 and the residue purified by column chromatography (SiO2, dichloromethane). The fractions were combined to afford crude 2-chloro-4-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, 101 mg. This material was taken onto the next step without further purification. LC @215 nm; Rt 2.52: 84%, m/z (ES+): 505 (M+H+.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[C:11]1[C:21]([NH2:22])=[N:20][C:14]2[N:15]=[C:16]([NH2:19])[N:17]=[CH:18][C:13]=2[CH:12]=1.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[NH2:19][C:16]1[N:17]=[CH:18][C:13]2[CH:12]=[C:11]([C:3]3[C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=[C:5]([CH3:9])[C:4]=3[CH3:10])[C:21]([NH:22][C:28]([NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[N:20][C:14]=2[N:15]=1
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cc(C)c(C)c(-c2cc3cnc(N)nc3nc2N)c1C
Product: Cc1cc(C)c(C)c(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c1C

Procedure:
The title compound was prepared from 0.3 g of 6-(2,3,5,6-tetramethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 98 and 0.125 mL of tert-butyl isocyanate according to Example 2. The product was purified by medium pressure liquid chromatography eluting with 1:1 CHCl3 :EtOAc; mp >300° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 393 (MH+, 55), 394 (MH+ +1, 13), 84 (100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:17]=[C:7]1[C:6]2[CH:18]=[C:2]([O:1][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:3]=[CH:4][C:5]=2[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), tert-butyl bromoacetate (0.88 g, 4.5 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for 12 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.44 g, 87%)
Reaction SMILES: S(O)(=O)(=O)C.[CH2:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15](=[O:28])[C:16]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([Br:26])[C:17]=1O)[CH3:7].[C:29](Cl)(=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>FC(F)(F)C(O)=O>[CH2:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15](=[O:28])[C:16]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([Br:26])[C:17]=1[C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH3:7]
Reactant: CCN1CCC[C@H]1CNC(=O)c1c(O)c(Br)cc(OC)c1OC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)c1c(Br)cc(OC)c(OC)c1C(=O)NC[C@@H]1CCCN1CC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3-bromo-2-hydroxy-5,6-dimethoxybenzamide mesylate (0.48 g, 1 mmol) in 10 ml of trifluoroacetic acid was added palmitoyl chloride (0.55 ml, 2 mmol). The reaction mixture was stirred at ambient temperature over molecular sieves for 20 h. After evaporation of the solvent in vacuo ether was added to the residue and filtered. The filtrate was washed several times with a saturated KHCO3 solution and dried (MgSO4). After evaporation of the solvent in vacuo the resulting oil crystallized on cooling. Yield 0.42 g (67%). M.p. 46°-48° C. Rf value is 0.21 for title compound and 0.32 for starting compound (SiO2, TLC-plates, 20% MeOH in i-Pr2O as eluent).
Reaction SMILES: [F:1][C:2]([F:48])([C:44]([F:47])([F:46])[F:45])[CH2:3][CH2:4]/[CH:5]=[C:6](\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[C:28]2[C:23](=[CH:24][C:25]([O:29]COC)=[CH:26][CH:27]=2)[O:22][CH2:21][C:20]1([C:34]1[CH:39]=[CH:38][C:37]([O:40]COC)=[CH:36][CH:35]=1)[CH3:33])/[C:7]([OH:9])=[O:8]>C(O)C.Cl.O>[F:48][C:2]([F:1])([C:44]([F:45])([F:46])[F:47])[CH2:3][CH2:4]/[CH:5]=[C:6](\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[C:28]2[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=2)[O:22][CH2:21][C:20]1([C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1)[CH3:33])/[C:7]([OH:9])=[O:8]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCC/C(=C\CCC(F)(F)C(F)(F)F)C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC/C(=C\CCC(F)(F)C(F)(F)F)C(=O)O
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (E)-6,6,7,7,7-pentafluoro-2-{9-[(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman-4-yl]nonyl}-2-heptenoic acid (111 mg, 0.16 mmol) in ethyl alcohol (5 ml), was added 6 N aqueous solution of hydrochloric acid (30 drops) and the reaction mixture was stirred at 40° C. for 6 h. The reaction mixture was diluted with water and extracted with methylene chloride. Organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuum. Crude product was purified by flash chromatography on silica gel (hexane:ethyl acetate:methyl alcohol=10:10:1), and then additionally by preparative thin-layer chromatography on Merck Silica-gel 60 plates (hexane:ethyl acetate:methyl alcohol=5:5:1) to give (E)-6,6,7,7,7-pentafluoro-2-{9-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methychroman-4-yl]nonyl}-2-heptenoic acid as a colorless amorphous solid. yield: 47.4 mg (49%)
Reaction SMILES: [Na].Cl[CH2:3][CH2:4][CH2:5][S:6]([NH:9][C:10]1[N:14]=[C:13]([C@H:15]([CH2:24][CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[O:12][N:11]=1)(=[O:8])=[O:7]>CO>[CH:27]1([CH2:26][CH2:25][CH2:24][C@@H:15]([C:13]2[O:12][N:11]=[C:10]([N:9]3[CH2:3][CH2:4][CH2:5][S:6]3(=[O:8])=[O:7])[N:14]=2)[CH2:16][C:17]([OH:19])=[O:18])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(NS(=O)(=O)CCCCl)no1
Agent: [Na]
Solvent: CO
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(N2CCCS2(=O)=O)no1
Temperature: 25 °C
Reaction time: 72 h
Yield: 105.3 %

Procedure:
Sodium metal (114 mg, 5.00 mmol) was added in portions to MeOH (10 ml) at 0° C. and stirred until all of the sodium had dissolved (˜10 minutes). A solution of tert-butyl(3R)-3-(3-{[(3-chloropropyl)sulfonyl]amino}-1,2,4-oxadiazol-5-yl)-6-cyclohexylhexanoate (preparation 45) (245 mg, 0.50 mmol) in MeOH (3 ml) was added to the reaction mixture and was stirred under a nitrogen atmosphere for 3 days warming to room temperature over this time. The reaction was quenched with H2O and the solvent removed under reduced pressure. The residue was diluted with water and acidified with 2M HCl (pH-3) and extracted with Et2O followed by EtOAc. The organic extracts were combined, dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (203 mg, 98%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([F:38])=[C:18]([NH:20][C:21]([C:23]2[N:27]3[CH:28]=[CH:29][C:30]([C:32]4[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=4)=[CH:31][C:26]3=[N:25][CH:24]=2)=[O:22])[CH:19]=1)=[O:13].[C:39]([OH:51])(=[O:50])[CH2:40][C:41]([CH2:46][C:47]([OH:49])=[O:48])([C:43]([OH:45])=[O:44])[OH:42]>C(O)C.CC(C)=O>[C:39]([OH:51])(=[O:50])[CH2:40][C:41]([CH2:46][C:47]([OH:49])=[O:48])([C:43]([OH:45])=[O:44])[OH:42].[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([F:38])=[C:18]([NH:20][C:21]([C:23]2[N:27]3[CH:28]=[CH:29][C:30]([C:32]4[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=4)=[CH:31][C:26]3=[N:25][CH:24]=2)=[O:22])[CH:19]=1)=[O:13]
Reactant: CC1CCCC(C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccnn4C)ccn23)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: CC(C)=O
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccnn4C)ccn23)c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
7-(2-Methyl-2H-pyrazol-3-yl)-imidazo[1,2-a]pyridine-3-carboxylic acid {5-[2-(2,6-dimethyl-piperidin-1-yl)-ethylcarbamoyl]-2-fluoro-phenyl}-amide (step 3) (480 g) was suspended in ethanol (2300 mL) in a 5000 mL four-necked flask equipped with thermometer, reflux condenser and a nitrogen inlet. The mixture was heated to 55° C. and the suspension gradually became clear. A solution of citric acid (180 g) in acetone (2.4 L) was added over 1 h and the internal temperature was controlled at 45-50° C. The clear solution was stirred at 50° C. for 2 h. A crystal seed (1 g) was added to the reactor and the internal temperature was cooled to 20° C. at a speed of 8° C./h. The mixture was stirred at 20° C. for 60 h. The resulting solid was filtered and the filter cake was washed with acetone (1 L) and dried in vacuum (under 4 mbar at 55° C.) for 24 h to afford the title compound;