Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26](OC)=[O:27])[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: COC(=O)c1cccc(Nc2nccc(-c3sc(N)nc3-c3ccccc3)n2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3cccc(CO)c3)n2)s1

Procedure:
To a suspension of N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-methoxycarbonyl-phenyl)-amine (800 mg, 2.0 mmol) in tetrahydrofuran (25 ml) is added a solution of sodium dihydro-bis(2-methoxyethoxy)aluminate in toluene (3 ml of a 3.5M solution) without cooling. The temperature of the reaction mixture rises to about +40° C. and the starting material dissolves immediately yielding a yellow clear solution. After an additional hour the solution is poured onto crushed ice and ammonium chloride. The colorless precipitate is filtered and washed with ethyl acetate and tetrahydrofuran. The organic phases are pooled, dried and concentrated under reduced pressure. Chromatography of the resulting solid gives the N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-hydroxymethyl-phenyl)-amine, m.p. 214–215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1>CN(C)C1C=CN=CC=1>[Cl:28][C:26]1[CH:25]=[C:24]([S:29]([NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[O:6])(=[O:30])=[O:31])[CH:23]=[C:22]([Cl:21])[CH:27]=1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1N
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccncc1
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Yield: 98 %

Procedure:
Prepared according to the procedure described for Example 116 using 3-amino-4-methoxy-N-(3,4-dichlorophenyl)-benzamide from Example 4 (0.932 g, 3.00 mmol), 3,5-dichlorobenzenesulfonyl chloride (0.737 g, 3.00 mmol) and 4-dimethylaminopyridine to afford the product (1.53 g); m.p. >230° C. (dec).
Reaction SMILES: [NH3:1].[F:2][C:3]1[C:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=[C:5](F)[N:4]=1>C(N)=O>[NH2:1][C:5]1[N:4]=[C:3]([F:2])[C:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: N
Reactant: O=C(OCc1ccccc1)c1ccc(F)nc1F
Solvent: NC=O
Product: Nc1ccc(C(=O)OCc2ccccc2)c(F)n1
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a stirred solution of ammonia (15 g) in formamide (250 ml) was added all at once benzyl 2,6-difluoropyridine-3-carboxylate (20 g, 0.08 mole). The mixture slowly became homogeneous, then a solid began to separate. After two hours, the mixture was poured into water (1000 ml) and the solid filtered. The solid was washed with several portions of water then air dried. Continuous extraction for one hour via a Soxhlet extraction apparatus using hexane as the solvent gave, after concentrating to 250 ml and cooling, 6.0 g (30%) of the desired benzyl 2-amino-6-fluoropyridine-3-carboxylate: m.p.=92°-94° C. The hexane insoluble material was recrystallized from a small volume of acetone to give 5.5 g (28%) of the isomeric benzyl 6-amino-2-fluoropyridine-3-carboxylate: m.p.=157.5°-159.5° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH:5]([CH2:7][OH:8])[NH2:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:34][CH:35]([CH3:39])[C:36](O)=[O:37].C(N(CC)CC)C>O.C(Cl)Cl>[F:34][CH:35]([CH3:39])[C:36]([NH:6][CH:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])=[O:37]
Reactant: CC(F)C(=O)O
Reactant: COC(=O)C(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(CO)NC(=O)C(C)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A rbf was charged with DL-serine methyl ester hydrochloride (1.49 g, 9.57 mmol, Sigma-Aldrich Chemical Company, Inc.), HATU (4.37 g, 11.49 mmol, Sigma-Aldrich Chemical Company, Inc.) and DCM (22 mL). 2-Fluoropropionic acid (0.75 ml, 9.57 mmol, Alfa Aesar, A Johnson Matthey Company) and triethylamine (3.3 ml, 23.93 mmol, Sigma-Aldrich Chemical Company, Inc.) were added and the reaction mixture was allowed to stir at rt overnight. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, aqueous saturated NaHCO3 solution, brine, and dried over MgSO4. The solution was concentrated in vacuo and the crude product was purified by silica gel chromatography, eluting with a gradient of 1% to 10% MeOH in DCM, to provide methyl 2-(2-fluoropropanamido)-3-hydroxypropanoate (0.69 g, 3.60 mmol, 38% yield).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([O:38][CH3:39])[CH:37]=1)[N:34]=[C:33]([CH:40]=O)[CH:32]=[CH:31]2>C(O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:40]/[C:33]2[CH:32]=[CH:31][C:30]3[C:35](=[C:36]([O:38][CH3:39])[CH:37]=[C:28]([F:27])[CH:29]=3)[N:34]=2)=[CH:8][CH:9]=1
Reactant: COc1cc(F)cc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Solvent: CCO
Product: COc1cc(F)cc2ccc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12

Procedure:
tert-Butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (200 mg, 0.533 mmol) and 6-fluoro-8-methoxyquinoline-2-carbaldehyde (109 mg, 0.533 mmol) were stirred in ethanol at ambient temperature for 24 hours. The reaction was concentrated and used as is in the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20](=[O:22])[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([C:24]([F:23])([F:32])[F:33])[CH:26]=3)=[CH:16][CH:17]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(CCC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc(CCC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ccn1
Yield: 31.8 %

Procedure:
A solution of 3-[4-({2-[(methylamino)carbonyl]pyridin-4-yl}oxy)phenyl]-propanoic acid (270 mg, 0.90 mmol), 3-(trifluoromethyl)aniline (158 mg, 0.98 mmol), HATU (409 mg, 1.07 mmol), and DIPEA (348 mg, 2.69 mmol) in DMF (5 mL) was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and washed with 1N HCl and brine. The organic solution was dried over MgSO4, filtered, and concentrated to give A-4 as a white solid (127 mg, 32%). 1H NMR (300 MHz, d6-DMSO) δ: 10.28 (s, 1H), 8.76 (m, 1H), 8.47 (d, 1H), 8.08 (br s, 1H), 7.75 (br d, 1H), 7.53 (t, 1H), 7.31-7.42 (m, 4H), 7.08-7.19 (m, 3H), 2.97 (t, 2H), 2.76 (d, 3H), and 2.71 (d, 2H). LCMS, FA: Rt=1.89 min, [MH+ 444.1].
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:5]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:4]=1[C:33]([O:35]C)=[O:34])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>ClC(Cl)C.C(OCC)(=O)C>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:3]([CH2:1][N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=[C:4]([C:33]([OH:35])=[O:34])[N:5]2[CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1c(C=O)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cccc2c1c(CN1CCOCC1)c(C(=O)O)n2CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 107C (50 mg) in dichloroethane (3 ml) was added sodium triacetoxyborohydride (35 mg) and morpholine (15 mg). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water, brine, and dried over Na2SO4. The residue was dissolved in tetrahydrofuran (4 ml), methanol (2 mL) and water (2 ml) and LiOH (100 mg) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue neutralized with aqueous NH4Cl and extracted with ethyl acetate (100 mL×3). The combined extracts were dried and concentrated to give crude product, which was purified by RPHPLC. 1H NMR (300 MHz, dimethyl sulfoxide-d6) δ 8.25 (m, 1H), 7.86 (m, 2H), 7.45 (m, 9H), 6.93 (m, 2H), 4.99 (m, 2H), 4.47 (m, 1H), 4.25 (t, 2H), 3.60 (m, 10H), 2.43 (m, 2H), 1.92 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1.NC1C=CC=CC=1.[C:30]([C:32]1[O:36][C:35]([C:37](O)=[O:38])=[CH:34][CH:33]=1)#[N:31].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd].CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:37]([C:35]3[O:36][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[O:38])=[C:10]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(C(=O)O)o1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCCCC3)c2)CC1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(NC(=O)c3ccc(C#N)o3)c(N3CCCCC3)c2)CC1

Procedure:
The procedure of Example 4, step (c) was followed using 304 mg (1.00 mmol) 1-methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine (as prepared in the previous step) and 304 mg of 10% palladium on carbon (50% by weight water) to prepare the intermediate aniline (4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine) along with 140 mg (1.02 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 178 μL (2.04 mmol) of oxalyl chloride, 10 μL of anh DMF, and 267 μL (1.53 mmol) of DIEA to perform the amide coupling. The resulting residue was chromatographed on a 20-g silica SPE column with 2-5% EtOH-dichloromethane to afford, after slow concentration from EtOAc-hexane (1:1), 232 mg (59%) of the title compound as a yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.53 (br s, 1H), 8.32 (d, 1H, J=8.9 Hz), 7.25 (d, 1H, J=3.7 Hz, partially obscured by CHCl3 peak), 7.21 (d, 1H, J=3.7 Hz), 6.80 (d, 1H, J=2.7 Hz), 6.73 (dd, 1H, J=8.9, 2.7 Hz), 3.20 (m, 4H), 2.85 (m, 4H), 2.59 (m, 4H), 2.36 (s, 3H), 1.80 (m, 4H), and 1.65 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. for C22H27N5O2, 394.2 (M+H), found 394.2.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.C(OC([NH:47][C@H:48]([C:50](O)=[O:51])[CH3:49])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)[C:50](=[O:51])[C@H:48]([CH3:49])[NH2:47])=[CH:17][CH:16]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](N)C(=O)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (251 mg, 0.46 mmol) and N-(tert-butoxycarbonyl)-L-alanine (97 mg, 0.51 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropylethylamine (0.24 mL, 1.38 mmol), 1-hydroxybenzotriazole hydrate (81 mg, 0.60 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (116 mg, 0.61 mmol) and the mixture was stirred at room temperature for 15 hours. The reaction was worked-up as described above to give the crude amide as a mixture of diastereomers. Purification and separation of the diastereomers was accomplished by column chromatography on silica gel (EtOAc) to afford a low polarity diastereomer (78 mg, 24%) and a high polarity diastereomer (48 mg, 15%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[CH3:7].C[N:16]([CH3:19])C=O>>[Cl:3][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:7][C:19]#[N:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1ccccc1
Reactant: CN(C)C=O
Product: N#CC=C(Cl)c1ccccc1
Yield: 53 %

Procedure:
The reaction of dimethylformamide, phosphorous oxychloride and acetophenone as described earlier gave the product as an oil (0.72 g, 53%). 1H NMR (400 MHz, CDCl3): δ 7.64-7.67 (2H, m), 7.43-7.53 (3H, m), 6.02 (1H, s).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:12][O:13][CH2:14][O:15][CH3:16])[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].Cl[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34]>CO.O>[CH2:36]([O:35][C:33]([N:1]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C@@H:2]([CH2:12][O:13][CH2:14][O:15][CH3:16])[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:34])[CH:37]=[CH2:38]
Reactant: COC(=O)CBr
Reactant: C=CCOC(=O)Cl
Reactant: COCOC[C@H](N)CCC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CCOC(=O)N(CC(=O)OC)[C@H](CCC(=O)OC(C)(C)C)COCOC
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of tert-butyl (4R)-4-amino-5-(methoxymethoxy)pentanoate (2.33 g, 10 mmol) and diisopropylethylamine (2.6 ml, 15 mmol) in methanol (70 ml) was dropped at room temperature methyl bromoacetate (1.4 ml, 15 mmol) in methanol (10 ml) and the mixture was stirred at 60° C. for 1 hour. Thereto were added additional methyl bromoacetate (0.5 ml, 5 mmol) and diisopropylethylamine (0.9 ml, 5 mmol). After stirring for 1 hour, the mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in chloroform (50 ml) and thereto was dropped allyl chloroformate (2.15 ml, 20 mmol) and then diisopropylethylamine (3.5 ml, 20 mmol). The mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour, respectively. Water was added thereto under cooling in an ice bath. The mixture was extracted three times with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel (51 g) chromatography (hexane/ethyl acetate: 2/1˜hexane/ethyl acetate: 1/1) to give tert-butyl (4R)-4-[[(allyloxy)carbonyl](2-methoxy-2-oxoethyl)amino}-5-(methoxymethoxy)pentanoate (3.01 g, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([Br:24])[C:22]=1[OH:23])[CH:18]=O.N1CCCCC1>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:18]\[C:17]1[CH:16]=[C:15]([Br:14])[C:22]([OH:23])=[C:21]([Br:24])[CH:20]=1
Reactant: O=C1Cc2cc(Br)ccc2C(=O)N1
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/c1cc(Br)c(O)c(Br)c1
Temperature: 95 °C
Yield: 99.6 %

Procedure:
6-Bromo-4H-isoquinoline-1,3-dione (0.12 g, 0.5 mmol), 3,5-dibromo-4-hydroxybenzaldehyde (0.14 g, 0.5 mmol), and piperidine (0.075 mL, 0.75 mmol) were dissolved in i-propanol (2 mL). After heating at 95° C. for 3 h, it is cooled, and the solid is filtered and washed with I-propanol, ether and hexane to yield 0.25 g (99.6%) solid; mp 167-168° C.; HRMS (ESI) m/z 499.8 (M−H)−1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]=[O:8].CC1N=C(C2C=N[C:30]([C:33](F)([F:35])[F:34])=[CH:31]C=2)SC=1CO.BrC(F)(F)C=C.[In]>CN(C)C=O>[F:34][C:33]([F:35])([CH:30]=[CH2:31])[CH:7]([C:6]1[S:5][C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1CO
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C=O
Agent: C=CC(F)(F)Br
Agent: [In]
Solvent: CN(C)C=O
Product: C=CC(F)(F)C(O)c1sc(-c2ccc(C(F)(F)F)nc2)nc1C
Reaction time: 3 h

Procedure:
To a solution of 5.0 g 4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazole-5-carbaldehyde (derived from [4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol according to the method described for 4-Methyl-2-(trans-1,4-trifluoromethyl-cyclohexyl)-thiazole-5-carbaldehyde) and 4.33 g 3-bromo-3,3-difluorpropene in 25 ml dimethylformamide. 2.11 g Indium were added and the resulting suspension was stirred in an ultrasonic bath for three hours. Then 20 ml 1N HCL were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 4.67 g 2,2-Difluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-but-3-en-1-ol as a colorless lyophilisate.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[CH3:22])[N:13]([S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:12]=1)C(=O)[O:4][C:5]([CH3:8])(C)C.[C:32]([O:35]CC)(=[O:34])[CH3:33].Cl.C[OH:40]>>[C:5]([OH:4])(=[O:40])/[CH:8]=[CH:33]/[C:32]([OH:35])=[O:34].[CH3:1][NH:2][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[CH3:22])[N:13]([S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH:12]=1
Reactant: CO
Reactant: Cc1ccncc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Reactant: CCOC(C)=O
Agent: Cl
Product: CNCc1cc(-c2cnccc2C)n(S(=O)(=O)c2cccnc2)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
tert-Butyl methyl{[5-(4-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate (230 mg) was dissolved in methanol (20 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added and the mixture was stirred at 70° C. for 20 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol (99:1→95:5) to give a free salt of the title compound. This was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (90 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 115 mg, 48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=S)[N:18]([CH:23]([C:25](OCC)=[O:26])[CH3:24])[C:17]=3[CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:30]=[C:17]3[C:16](=[CH:15][CH:14]=2)[O:21][CH2:20][C:19]2[N:18]3[CH:23]([CH3:24])[C:25](=[O:26])[NH:32][N:33]=2)[CH2:11]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 49.4 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester (0.530 g, 1.22 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.486 g, 9.72 mmol) and the mixture was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.234 g, 52%) as a white solid. LC/MS (Table 1, Method 3) Rt=1.332 min.; MS m/z: 389 [M+H]+.
Reaction SMILES: [C:1]([CH:4](C)[C:5](=O)[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=O)C.Cl.[NH2:16][CH:17]([C:23](O)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:26]([O-])(=O)C.[Na+].C(=O)=O>C(O)(=O)C>[CH2:21]([O:20][C:18]([C:17]1[NH:16][C:4]([CH3:1])=[C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:23]=1[CH3:26])=[O:19])[CH3:22]
Reactant: CCOC(=O)CCC(=O)C(C)C(C)=O
Reactant: CCOC(=O)C(N)C(=O)O
Reactant: CC(=O)[O-]
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1c(C)[nH]c(C(=O)OCC)c1C
Temperature: 99 °C
Yield: 65.8 %

Procedure:
To a 5 L three-neck flask equipped with a thermometer and a mechanical stirrer and heated on a steam bath was added 350 g ethyl 5-acetyl-4-oxohexanoate, 329 g ethyl aminomalonate hydrochloride, 133 g sodium acetate and 1.2 L acetic acid. The mixture was heated to 99° C. over 37 minutes. By 62° C., carbon dioxide evolution was already rapid. After a total of 35 minutes at 99° C. gas, CO2 evolution had greatly slowed. After another hour, the mixture was cooled, sodium chloride removed by vacuum filtration, and the solvent evaporated. The residue was mixed with 1 L of cold water. The precipitate was collected by vacuum filtration, washed with 400 mL water, and dissolved in 1 L of hot 95% ethanol. The solution was treated with 20 g of Darco G-60, hot-filtered, and cooled to room temperature. The crystalline solid was collected by vacuum filtration, washed twice on the filter with 200 mL of 50% ethanol and dried under vacuum at 70° C. to give 285 g (64% yield) of 2-ethoxycarbonyl-4-(2-ethoxycarbonylethyl)-3,5-dimethylpyrrole. The filtrate was refrigerated overnight to give another 53.1 g (11.9% yield) of product for a total yield of 75.9%).
Reaction SMILES: CC[O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=O.C(O)C.[CH3:16][NH:17][CH3:18]>>[CH3:16][N:17]([CH3:18])[C:4]([CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1=[O:12])=[O:3]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=O)C1CCCCC1=O
Temperature: 0 °C

Procedure:
0.313 mol (50 ml) of ethyl cyclohexanone-2-carboxylate and 140 ml 33% dimethylamine in ethanol (about 0.78 mol dimethylamine) were stirred in a pressure reactor for 12 hours at 110° C. After cooling the reaction mixture was concentrated on a rotary evaporator, the residue was dissolved in 500 ml ethyl acetate and the organic phase was washed with 200 ml of 1 M NaOH and 3×50 ml water. The organic phase was then evaporated on a rotary evaporator to dryness. 46 g of the crude product was dissolved in 100 ml tert-butyl methyl ether and cooled to 0° C. Precipitated product was filtered off and dried, 3.6 g of the title compound were obtained.