Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16](Cl)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:23](O)(=[O:25])C.CCCCCC>CO.ClCCl>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([O:25][CH3:23])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)n2nc(SCc3ccccc3)nc2c1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(C)cc2nc(SCc3ccccc3)nn12
Reaction time: 4 h

Procedure:
A mixture of 2-benzylthio-5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridine (5.0 g, 0.017 mol), sodium methoxide in methanol (16 mL of 25 percent, 3.7 g, 0.070 mol) and methanol (100 mL) were heated at reflux with stirring for 4 hours. The reaction mixture was then cooled, acidified with acetic acid (10 mL), and concentrated by evaporation under reduced pressure. The residue obtained was dissolved in dichloromethane and the resulting solution was washed well with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue obtained was mixed with hexane and filtered to recover the solids. The solids were dried to obtain 4.7 g (97 percent of theory) of the title compound as a tan powder melting at 85°-87° C.
Reaction SMILES: C(N)C.[CH3:4][Si:5]([C:8]#[CH:9])([CH3:7])[CH3:6].[CH2:10]([S:17]/[C:18](/I)=[CH:19]\[CH:20]=[C:21](/[S:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)\[Sn:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>C1C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:42]([S:41]/[C:21](/[Sn:22]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:20]\[CH:19]=[C:18](\[S:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:9]#[C:8][Si:5]([CH3:7])([CH3:6])[CH3:4])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: C#C[Si](C)(C)C
Reactant: I/C(=C/C=C(\SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)SCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCN
Solvent: c1ccccc1
Solvent: ClCCl
Product: C[Si](C)(C)C#C/C(=C\C=C(/SCc1ccccc1)[Sn](c1ccccc1)(c1ccccc1)c1ccccc1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 38 h
Yield: 86.3 %

Procedure:
A mixture of EtNH2 (1 mL) and trimethylsilylethyne (32 mL, 0.23 mmol) were added to a solution of 5 (0.148 g, 0.190 mmol), CuI (1.81 mg., 0.0095 mmol) and (Ph3P)2PdCl2 (6.67 mg, 0.0095 mmol) in benzene (3 mL) under argon. The resulting yellow-green solution was stirred at room temperature for 38 h, and then concentrated in vacuo. The residue was mixed with ether (20 mL) and water (5 mL), the layers were separated and the aqueous layer was extracted by ether (2×10 mL). The combined ether layers were washed with NH4Cl solution (2×25 mL) and water (10 mL), dried (MgSO4), and concentrated in vacuo. Flash column chromatography (1:6 CH2Cl2 :hexanes) of the dark, oily residue gave 7 as a yellow solid (122 mg, yield 86%): mp 122°-123° C.; 1H NMR δ 6.9-7.8 (m, 27 H), 4.06, 37.27, 0.03; Anal. Calcd for C41H40S2SiSn, C, 66.21; H, 5.42. Found, C, 66.42; H, 5.55.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@@H:6]2[CH2:9][OH:10].C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:10][CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]3[CH2:8][C@@H:7]2[C:2]3([CH3:11])[CH3:1])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)[C@H]2CC[C@H](CO)[C@@H]1C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol (7.0 mL, 44.2 mmol) and triethylamine (13.5 mL, 97.0 mmol) in dichloromethane (60 mL) was cooled to 0° C. A solution of 4-methylbenzene-1-sulfonyl chloride (10.9 g, 57.4 mmol) in dichloromethane (20 mL) was added drop wise at 0° C. The reaction was stirred at room temperature for 16 hours. The mixture was washed with saturated aqueous NaHCO3 and the aqueous layer was extracted twice with dichloromethane. The organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[F:36][C:37]1[CH:38]=[N:39][C:40]([O:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:41]([CH:51]=1)[C:42]([NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:43].CN1CCOCC1>CN(C)C=O>[F:36][C:37]1[CH:38]=[N:39][C:40]([O:52][C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[C:41]([CH:51]=1)[C:42]([NH:44][CH:45]1[CH2:46][CH2:47][N:48]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[OH:11])[CH2:49][CH2:50]1)=[O:43]
Reactant: O=C(NC1CCNCC1)c1cc(F)cnc1Oc1ccc(F)cc1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)N2CCC(NC(=O)c3cc(F)cnc3Oc3ccc(F)cc3)CC2)c(O)c1
Yield: 66.8 %

Procedure:
4-Methylsalicylic acid (91 mg, 0.595 mmol), 1-hydroxybenzotriazole hydrate (110 mg, 0.811 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (135 mg, 0.703 mmol), 5-fluoro-2-(4-fluoro-phenoxy)-N-piperidin-4-yl-nicotinamide hydrochloride (200 mg, 0.541 mmol) (see Preparation 29) and N-methyl morpholine (0.12 ml, 1.08 mmol) were stirred in N,N-dimethylformamide (4 ml) under an atmosphere of nitrogen at room temperature for 18 hours. The reaction mixture was then partitioned between ethyl acetate (10 ml) and water (10 ml), the organic layer separated, washed with a saturated aqueous solution of sodium chloride (10 ml) and dried over anhydrous magnesium sulphate. The solvent was then removed in vacuo and the residue purified via flash column chromatography on silica gel eluting with a solvent gradient of 100% dichloromethane changing to 99:1, by volume, dichloromethane:methanol. The resulting white foam was triturated with pentane (5 ml) giving 5-fluoro-2-(4-fluoro-phenoxy)-N-[1-(2-hydroxy-4-methyl-benzoyl)-piperidin-4-yl]-nicotinamide (169 mg) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:27]([C@H:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[N:30]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:28]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[C@H:15]([CH3:16])[C@H:27]([C@H:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[N:30]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[OH:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a solution of (R)-4-benzyl-3-propionyloxazolidin-2-one (1.0 equiv.) in DCM (0.13 M) was added TiCl4 (1.0 equiv.) at −40° C. The mixture was stirred at 40° C. for 10 min (yellow suspension), then DIPEA (2.5 equiv.) was added (dark red solution) and stirred at 0° C. for 20 min. (R)-tert-butyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate (1.0 equiv.) in DCM (0.5 M) was then added dropwise and the resulting mixture was stirred for 1.5 hours. The reaction was quenched by the addition of aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic phase was separated, washed with brine, dried with magnesium sulfate, filtered, and concentrated. The residue was purified via column chromatography eluting with ethyl acetate and hexanes (1:4) to give (R)-tert-butyl 4-((1R,2R)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-2-methyl-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate as the major product (5:2) in 58% yield. LC/MS=363.3 (M+H-Boc), Rt=1.09 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5[CH2:41]CCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CC[CH2:48][C@H:47]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH:37]([CH3:41])[CH2:47][CH3:48])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:12])=[O:11])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Reactant: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)CNCc1cc(F)cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 54.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 30.5 mg of the title compound (54.5%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)=[O:7])(=[O:4])=[O:3]>C(O)C.[Pd].O>[CH3:1][S:2]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)=[O:7])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cccc(N)c1
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To a suspension of 1-(methylsulphonylaminocarbonyl)-3-nitrobenzene (4 g, 16 mmol) in ethanol (100 ml) was added 10% palladium on carbon (0.5 g, 12.5% (w/w)) in water (5 ml). The mixture was hydrogenated at 40 psi for 10 min then the catalyst was filtered off and washed with ethanol. The solvent was evaporated in vacuo to give the title compound (2.9 g, 83%) as a tan powder after trituration with diethyl ether, mp 153°-155° C. 1H NMR (360 MHz, D6 -DMSO) δ 3.3 (3H, s), 6.79 (1H, d, J=7.7 Hz), 7.05 (1H, d, J=7.7 Hz), 7.08 (1H, d, J=1.9 Hz), 7.13 (1H, dd, J=7.7 and 7.7 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.[SH:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[NH:23][C:19]=1[S:18][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: NC(N)=Nc1nc(-c2cccc(CCl)n2)cs1
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(N)=Nc1nc(-c2cccc(CSc3nc4ccccc4[nH]3)n2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
A mixture of 4-(6-chloromethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (1.1 g), 2-mercaptobenzimidazole (0.74 g) and potassium carbonate (0.68 g) in N,N-dimethylformamide (20 ml) was stirred for 15 hours at ambient temperature. The reaction mixture was added water and extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated to give 4-[6-(benzimidazol-2-yl)thiomethylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole (1.22 g).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[CH2:8]([O:10][C:11](=[O:40])[C@@H:12]([CH:19](COC(=O)C)[C:20]1[CH:25]=[CH:24][C:23]([NH:26]C(OC(C)(C)C)=O)=[C:22]([CH3:34])[CH:21]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:9].Cl[CH2:42]Cl>>[CH2:8]([O:10][C:11](=[O:40])[C@H:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([CH3:34])[C:21]=1[CH2:42][O:5][C:3](=[O:4])[CH3:2])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C[C@@H](C(=O)OCC)C(COC(C)=O)c1ccc(NC(=O)OC(C)(C)C)c(C)c1
Reactant: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(N)c(C)c1COC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of 2-(R)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinic acid diethyl ester (525 mg, 1.1 mmol) in dichloromethane (10 mL). Reaction mixture was stirred at room temperature for 1 hour. Mixture was concentrated in vacuo. Residue was treated with aqueous sodium bicarbonate and extracted with ethyl acetate (2× 20 mL). Combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. The title compound was obtained as amber oil in 99% yield. MS m/e (M−C2H4O2+H)−=306.1.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.[Na].[CH3:15][SH:16]>C(Cl)Cl.CN1C(=O)CCC1>[CH3:15][S:16][CH2:3][CH:2]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[OH:1]
Reactant: CS
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CSCC(O)C1CCC2(CC1)OCCO2
Temperature: 80 °C

Procedure:
8-(oxiran-2-yl)-1,4-dioxaspiro[4.5]decane (202 mg, 1.10 mmol), prepared in the previous step, in DCM (20 mL) was dissolved in NMP (20 mL) and methanethiol sodium salt (297 mg, 4.24 mmol) was added. The mixture was stirred, heating to 80° C. under argon overnight and then cooled to ambient temperature and poured onto water. After extraction with ethyl acetate, the organic layers were concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0-50% ether) to afford the product.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11]N2C(=O)CCC2=O)=O)=[C:7]([Cl:21])[CH:6]=1)=[N+:2]=[N-:3].Cl.[C:23]([NH:31][CH2:32][C@@H:33]([C:35]([O:37][CH3:38])=[O:36])[NH2:34])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:34][C@H:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32][NH:31][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:11])=[C:7]([Cl:21])[CH:6]=1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Reactant: [N-]=[N+]=NCc1ccc(C(=O)ON2C(=O)CCC2=O)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Yield: 69.6 %

Procedure:
A solution of 1-[[4-(azidomethyl)-2-chlorobenzoyl]oxy]-2,5-pyrrolidinedione (4.64 g, 15.0 mmol), 3-(benzoyl)amino-L-alanine, methyl ester hydrochloride (4.00 g, 15.5 mmol), and triethylamine (4.00 g, 39.5 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 h. The solvent was evaporated, and 1 M HCl (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), dried (MgSO4), filtered, evaporated, and chromatographed (50–75% ethyl acetate/hexanes) to give N-[4-(azidomethyl)-2-chlorobenzoyl]-3-(benzoyl)amino-L-alanine, methyl ester (4.34 g, 69%) as a colorless oil that solidified on standing, mp 112–114° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:28])([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]1[O:41]C(C)(C)[O:39][C:38](=O)[CH:37]=1>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:28][C:38](=[O:39])[CH2:37][C:36]([C:32]1[S:33][CH:34]=[CH:35][C:31]=1[Cl:30])=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2sccc2Cl)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1NC(=O)CC(=O)c1sccc1Cl
Yield: 54.1 %

Procedure:
Prepared from [2-amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamic acid tert.-butyl ester (Example G30) (216 mg, 0.55 mmol) and 6-(3-chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J2) (142 mg, 0.58 mmol) according to the general procedure K. Obtained as a beige solid (172 mg).
Reaction SMILES: [F:1][C:2]([CH:9]=[CH:10][CH:11]([F:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7][OH:8].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[F:1][C:2](=[CH:9][CH:10]=[C:11]([F:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:3]=[CH:4][CH:5]=[CH:6][C:7]([OH:26])=[O:8]
Reactant: CCCCCCCCCCCC(F)C=CC(F)=CC=CC=CO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCCCCCCCCCCC(F)=CC=C(F)C=CC=CC(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To a solution of the alcohol prepared in 3P (282 mg, 0.86 mmoles) in acetone (7 ml) cooled to 0° C. was added dropwise 2.67M Jones reagent over 15 min. until the orange color was stable. The mixture was stirred 15 min. at 0° C. The excess of Jones reagent was reacted with isopropanol. The acetone was evaporated under reduced pressure without heating. The residue was taken up with water and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to leave an oil. Flash chromatography on silica gel and elution with a 15:85 mixture of ethyl acetate and benzene gave pure acid (180 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]>>[ClH:1].[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[CH:3][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCC(O)CO
Reactant: Clc1ccc2c(Cl)cc(-c3ccccc3)nc2c1
Product: Cl
Product: OCC(O)CNc1cc(-c2ccccc2)nc2cc(Cl)ccc12

Procedure:
The title compound, m.p. 234-236° C., and MS: m/e=328 (M+), was prepared from 4,7-dichloro-2-phenyl-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11].[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:8]([O:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][C:26]([F:25])([F:35])[F:36])=[CH:29][CH:30]=2)=[C:9]([CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11]
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)ccc1F
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(F)ccc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 3.1 %

Procedure:
Cs2CO3 (146.6 mg, 0.45 mmol) was added to a solution of 2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (37.5 mg, 0.15 mmol) and 4-trifluoro methoxyphenol (80.1 mg, 0.45 mmol) in DMF (0.9 mL) and the reaction was stirred at 100° C. for 8 hours. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide (101) (1.9 mg, 3%). ESI-MS m/z calc. 408.07. found 409.3 (M+1)+; Retention time: 1.68 minutes (3 minutes run).
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C.FC(F)(F)C(O)=O.[F:41][C:42]([F:70])([F:69])[CH2:43][N:44]1[C:48]([C:49]2[N:58]=[C:57]3[N:51]([CH2:52][CH2:53][O:54][C:55]4[CH:62]=[C:61]([NH:63][CH:64]([CH3:68])[C:65]([OH:67])=O)[CH:60]=[CH:59][C:56]=43)[CH:50]=2)=[N:47][CH:46]=[N:45]1>CN(C=O)C>[F:41][C:42]([F:69])([F:70])[CH2:43][N:44]1[C:48]([C:49]2[N:58]=[C:57]3[C:56]4[CH:59]=[CH:60][C:61]([NH:63][C@@H:64]([CH3:68])[C:65]([NH2:2])=[O:67])=[CH:62][C:55]=4[O:54][CH2:53][CH2:52][N:51]3[CH:50]=2)=[N:47][CH:46]=[N:45]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(Nc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](Nc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Reaction time: 18 h
Yield: 29.5 %

Procedure:
HATU (179 mg, 0.47 mmol), ammonium chloride (50 mg, 0.942 mmol) and triethylamine (0.22 mL, 1.57 mmol) were added to a solution of (S)-2-{2-[2-(2,2,2-trifluoro-ethyl-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino}-propionic acid trifluoroacetate salt (168 mg, 0.314 mmol) in DMF (3 mL) and stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue treated with ethyl acetate and water, the organics layer separated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM), then trituration in water to give 529 (39 mg, 30%). LCMS: RT=3.23 min, [M+H]+=422. 1H NMR 400 MHz (DMSO-d6): δ 8.05 (1 H, s), 7.91 (1 H, s), 7.40 (1 H, br, s), 7.01 (1 H, br, s), 6.46 (1 H, dd, J=8.86, 2.33 Hz), 6.25 (1 H, d, J=7.11 Hz), 6.13 (1 H, d, J=2.29 Hz), 5.92 (2 H, q, J=8.89 Hz), 4.46-4.39 (4 H, m), 3.81 (1 H, t, J=6.96 Hz), 1.32 (3 H, d, J=6.87 Hz)
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:12]1[N+:17]([O-:18])=[C:16]2[CH2:19][CH2:20][CH2:21][C:15]2=[C:14]([Cl:22])[CH:13]=1>O1CCOCC1.C(Cl)Cl>[Cl:22][C:14]1[CH:13]=[C:12]([O:4][CH:1]([CH3:3])[CH3:2])[N+:17]([O-:18])=[C:16]2[CH2:19][CH2:20][CH2:21][C:15]=12
Reactant: [O-][n+]1c(Cl)cc(Cl)c2c1CCC2
Reactant: CC(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)Oc1cc(Cl)c2c([n+]1[O-])CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of iso-propanol (0.047 g, 0.79 mmol) in dioxane (3 mL) at rt was added potassium tert-butoxide (0.053 g, 0.47 mmol). The mixture was stirred at rt for 30 min. Then, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.100 g, 0.39 mmol) in dioxane (1 mL) was added and the mixture was heated under microwave irradiation to 100° C. for 30 min. After this time, the mixture was diluted with methylene chloride and washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.079 g, 88%) as a white solid. MW=227.69. 1H NMR (CDCl3, 300 MHz) δ 6.73 (s, 1H), 4.90-4.85 (m, 1H), 3.23 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H), 1.44 (d, J=6.0 Hz, 6H); APCI MS m/z 228 [M+H]+.