Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23]([C:29](O)=[O:30])=[N:22]2)=[CH:16][CH:15]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][C@H:62]([CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C@@H:63]([OH:67])[C:64]([OH:66])=[O:65].Cl.CCN(C(C)C)C(C)C>>[C:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23]([C:29]([NH:61][C@H:62]([CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:63]([OH:67])[C:64]([OH:66])=[O:65])=[O:30])=[N:22]2)=[CH:16][CH:15]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)nc1
Reactant: N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(=O)N[C@H](Cc2ccccc2)[C@@H](O)C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)nc1
Temperature: 40 °C
Yield: 91 %

Procedure:
A solution of 1-[6-(2-acetylsulfamoylphenyl)pyridin-3-ylmethyl]-5-propyl-1H-pyrazole-3-carboxylic acid (100 mg, 226 μmol) in DMF (7.0 mL, 90 mmol) was added to HATU (85.9 mg, 226 μmol). The resulting mixture was stirred for 5 minutes before (2R,3R)-3-amino-2-hydroxy-4-phenylbutyric acid.HCl (52.4 mg, 226 μmol) and DIPEA (315 μL, 1.8 mmol) were added. The resulting solution was heated at 40° C. overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (48 mg; 91% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C31H33N5O7S, 620.21; found 620.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(Br)cc2)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccc(Br)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 35.9 %

Procedure:
To a solution of ethyl 2-[(4-bromophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.46 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.067 g, 0.46 mmol) in ethanol (5.0 mL), piperidine (0.85 mL, 0.92 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound (0.075 g, y. 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][O:13][C:14]2[C:22]([F:23])=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:24])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(N(C(C)C)C(C)C)C.[CH3:34][N:35]([CH3:40])[S:36]([NH2:39])(=[O:38])=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][O:13][C:14]2[C:22]([F:23])=[CH:21][C:17]([C:18]([NH:39][S:36]([N:35]([CH3:40])[CH3:34])(=[O:38])=[O:37])=[O:19])=[C:16]([F:24])[CH:15]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ncc(COc2cc(F)c(C(=O)O)cc2F)cc1Cl
Reactant: CN(C)S(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ncc(COc2cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc2F)cc1Cl
Reaction time: 18 h

Procedure:
To 4-((5-chloro-6-isopropoxypyridin-3-yl)methoxy)-2,5-difluorobenzoic acid (Preparation 9, 0.05 g, 0.14 mmol) in solution in DCM (5 mL) is added WSCDI (0.04 g, 0.21 mmol), DMAP (0.026 g, 0.21 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.09 mL, 0.42 mmol). After 10 minutes was added N,N-dimethylsulfamide (0.026 g, 0.21 mmol) and the reaction was left at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and purified using reverse phase preparative HPLC to afford the title compound.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15].O>C(O)C>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCCO
Reactant: ClCC=Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN(C/C=C/c1ccccc1)CCO

Procedure:
12.5 Grams of cinnamyl chloride and 21 g of 2-methylaminoethanol were dissolved in 100 ml of ethanol, and the solution was refluxed for 5 hours. The solvent was removed by evaporation, to the residue thus obtained was added water and washed with n-hexane. To the water layer was added 3N-sodium hydroxide aqueous solution to adjust its pH to 10-11, and extracted with ether. The ether extract was washed with water and dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was purified by means of a silica gel column chromatography (eluent: chloroform:methanol=25:1) to yield 15 g of 2-[N-methyl-N-(3-phenyl-2(E)-propenyl)amino]ethanol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine. P-157
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7]>C1COCC1>[N:22]1[CH:23]=[CH:24][C:19]([C:16]2[N:15]=[C:14]([C@H:11]3[CH2:10][CH2:9][C@H:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[O:18][N:17]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)C1CCC(c2nc(-c3ccncc3)no2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](c2nc(-c3ccncc3)no2)CC1
Temperature: 60 °C

Procedure:
Water (0.5 ml) and lithium hydroxide (9.2 mg, 0.22 mmol) were added to a stirred solution of 4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexanecarboxylic acid methyl ester (Preparation 3, 30 mg, 104 μmol) in THF (1.5 ml). The mixture was heated at 60° C. for 1.5 h, cooled and the THF removed in vacuo. Water (5 ml) was added, the aqueous washed with EtOAc (5 ml) and carefully acidified with 1M HCl to pH 4. The resulting precipitate was extracted into 3% MeOH in EtOAc (2×15 ml) and the combined organic phases dried (MgSO4) and evaporated to afford the title compound: RT=2.74 min, m/z (ES+)=274.2 [M+H]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH:21]([C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1)=[CH2:22]>>[O:31]1[CH2:32][CH2:33][N:28]([CH2:27][C:26]2[CH:34]=[CH:35][C:23](/[CH:21]=[CH:22]/[C:2]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=4)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=3)=[CH:24][CH:25]=2)[CH2:29][CH2:30]1
Reactant: C=Cc1ccc(CN2CCOCC2)cc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccc(CN3CCOCC3)cc2)c2ccc(C=O)cc21

Procedure:
According to the method of example A57A, 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (402 mg, 1 mmol) was reacted with 4-(4-vinylbenzyl)morpholine (304 mg, 1.5 mmol) to give the title compound upon silica gel purification (1:1 hexane/ethyl acetate) as a yellow solid (120 mg, 25%). MS ESI 478.3 [M+H]+, calcd for [C27H35N3O3Si+H]+ 478.2.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]([CH3:29])[CH:24]([CH3:28])[C:25]([OH:27])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[Br:30][C:31]1[CH:36]=[C:35]([NH2:37])[N:34]=[C:33]([NH2:38])[CH:32]=1.CN1C(=O)CCC1>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[N:23]([CH:24]([C:25](=[O:27])[NH:38][C:33]1[CH:32]=[C:31]([Br:30])[CH:36]=[C:35]([NH2:37])[N:34]=1)[CH3:28])[CH3:29])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Nc1cc(Br)cc(N)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C(=O)Nc1cc(Br)cc(N)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
N,N′-dicyclohexylcarbodiimide (24.7 g, 120 mmol) is added slowly to a mixture of 2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid (39 g, 192 mmol) in DCM (60 ml) with ice bath cooling. Stirring is continued and the mixture warmed to RT. The mixture is stirred at RT for 30 minutes before 4-bromopyridine-2,6-diamine A (15 g, 80 mmol) in 60 ml DCM and 10 ml NMP is added dropwise. After stirring for 3 days at RT the reaction mixture is diluted with DCM, filtered and extracted with a saturated aqueous sodium hydrogencarbonate solution. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 19.8 g (67%). HPLC-MS: M+H=373/375; tR=0.93 min (Method—2).
Reaction SMILES: C1(N2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)C=N2)C=CC=CC=1.C(C1C=C2C(=CC=1)/C(=N/O)/CCC2)=C.[C:45]1([C:51]2C(C(F)(F)F)=C(C(OC)=O)[S:53][N:52]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:45]1([C:51]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)[S:53][N:52]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: COC(=O)c1snc(-c2ccccc2)c1C(F)(F)F
Agent: C=Cc1ccc2c(c1)CCC/C2=N\O
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1snc(-c2ccccc2)c1C(F)(F)F

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89A employing 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1) and methyl 3-phenyl-4-(trifluoromethyl)isothiazole-5-carboxylate (Preparation 103E) as starting materials. The compound had an HPLC retention time=4.25 min. (condition C); LC/MS M+1=424.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:11]2[NH:12][C:13]([C:15]([O:17]C)=[O:16])=[CH:14][C:10]=2[CH2:9][CH2:8]1.[OH-].[Li+].CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:11]2[NH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:10]=2[CH2:9][CH2:8]1
Reactant: COC(=O)c1cc2c([nH]1)C(Cc1cccc(OC)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(CC2CCc3cc(C(=O)O)[nH]c32)c1

Procedure:
The title compound was synthesized from methyl 6-(3-methoxybenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (127 mg, 0.45 mmol) and lithium hydroxide (188 mg, 4.50 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 80 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.10-2.21 (m, 1H) 2.53-2.76 (m, 4H) 2.91-2.99 (m, 1H) 3.34-3.44 (m, 1H) 3.82 (s, 3H) 6.72-6.77 (m, 2H) 6.78-6.86 (m, 2H) 7.24-7.31 (m, 2H) 8.28 (br. s., 1H). LCMS m/e 272 (M+H). Purity>99% (HPLC).
Reaction SMILES: Br[CH2:2][C:3]([CH3:7])=[C:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:14][C:15]1([CH3:27])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[O:16]1>CN(C=O)C.C(OCC)C>[CH3:7][C:3](=[C:4]([CH3:6])[CH3:5])[CH2:2][N:25]1[CH:26]=[C:22]([B:17]2[O:16][C:15]([CH3:27])([CH3:14])[C:19]([CH3:21])([CH3:20])[O:18]2)[CH:23]=[N:24]1
Reactant: CC(C)=C(C)CBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)=C(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
1-Bromo-2,3-dimethylbut-2-ene (3.78 g, 23.19 mmol), and cesium carbonate (15.11 g, 46.4 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.0 g, 15.46 mmol) in DMF (52 mL), and the mixture was stirred at 90° C. for 18 h. The mixture was allowed to cool to room temperature, diluted with diethyl ether, washed with water (3×50 mL) and brine. The organic layers were separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-40% EtOAc/hexane) to afford 1-(2,3-dimethylbut-2-en-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 7.62 (s, 1H), 4.74 (s, 2H), 1.83 (s, 3H), 1.74 (s, 3H), 1.59 (s, 3H), 1.31 (s, 12H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)=[O:16]
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C(Cl)CCCCCl
Product: O=C(CCCCCl)c1ccc2c(c1)CCO2

Procedure:
Using 2,3-dihydro-1-benzofuran (24.5 g) and 5-chlorovaleryl chloride (34.8 g) according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals (32.4 g) having a melting point of 56 to 57° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:21]COC)[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH:10](CCl)[CH2:9]1)=[O:7])(C)(C)C.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+].[Cl:39]C(OC)=O>O>[Cl:39][CH:10]1[C:11]2[C:16](=[CH:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]=2[OH:21])[N:8]([C:6]([O:5][CH3:1])=[O:7])[CH2:9]1
Reactant: COC(=O)Cl
Reactant: COCOc1c2c(cc3ccccc13)N(C(=O)OC(C)(C)C)CC2CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)N1CC(Cl)c2c1cc1ccccc1c2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A solution of 28 (11 mg, 29.1 μmol) was treated with 1.0 mL of 3.6 N HCl/EtOAc and the resulting solution was stirred for 30 min at 25° C. The solvent was removed by a stream of N2 and the residual salt was dried under vacuum. This salt was suspended in 0.6 mL of anhydrous THF and treated with NaHCO3 (5.4 mg, 64.1 μmol, 2.2 equiv) and ClCO2CH3 (4.5 μL, 58.2 μmol, 2.0 equiv) and the mixture was stirred for 3 h at 25° C. Upon completion, the reaction mixture was diluted with 10 mL of H2O extracted with EtOAc (3×10 mL), dried (Na2SO4) and concentrated in vacuo. Flash chromatography (SiO2, 1.5×15 cm, 0-40% EtOAc/hexane gradient) provided pure 32 (5.5 mg, 65%) as a white solid: 1H NMR (CDCl3, 400 MHz ) δ7.86 (d, J=8.2 Hz, 1H), 7.86 (br s, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.42 (m, 1H), 7.35 (m, 1H), 5.80 (s, 1H), 4.11 (m, 2H), 4.01-3.87 (m, 5H), 3.63 (app t, J=9.4 Hz, 1H); IR (film) νmax3379, 2956, 1673, 1435, 1372, 1283, 1218 cm−1; FABHRMS (NBA/NaI) m/z 291.0656 (M+, C15H14ClNO3 requires 291.0662).
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[C:7]([Cl:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1>C(OC)(C)(C)C>[NH2:1][C:3]1[N:8]=[C:7]([Cl:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1
Reactant: N
Reactant: FC(F)(F)Oc1cc(Cl)nc(Cl)n1
Solvent: COC(C)(C)C
Product: Nc1nc(Cl)cc(OC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.3 g (0.25 mol) of gaseous ammonia were passed over the course of 45 minutes into a stirred mixture of 23.3 g (0.1 mol) of 2,4-dichloro-6-trifluoromethoxypyrimidine and 150 ml of methyl tert.-butyl ether at −50 to −45° C. The mixture was stirred at −50° C. for 30 minutes, at −30° C. for 1 hour and at 25° C. for 1 hour. The precipitate was filtered off with suction, washed with water and dried, resulting in 5.4 g (33.1% of theory) of 4-amino-2,4-dichloropyrimidine of melting point 270-272° C. as by-product. The filtrate was washed with water, dried and concentrated under reduced pressure, and the residue was chromatographed with 5:1 petroleum ether/ether, the initial fractions yielding 3 g (12.8% of theory) of starting material as a colorless oil, and subsequent fractions containing 9 g (42% of theory) of the title compound as colorless crystals of melting point 55-56° C. Conversion was 48.3%.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[NH:3]1.N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCOCC>[C:25]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=2)[CH2:10][CH2:11][C:2]1([CH3:18])[CH3:1])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)CCC(C)(C)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)C(C)c1ccc2c(c1)CCC(C)(C)N2C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
3.0 g of methyl 2-(1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 11) were added to 30 ml of pyridine, and 2.6 g of benzoyl chloride was further added to the solution. The mixture was stirred at room temperature for 15 hours, followed by addition of ice-water and extraction with ether. The ethereal solution was washed with 10% hydrochloric acid, water and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Ether was distilled off to give 3.9 g of methyl 2-(1-benzoyl-1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 17).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH:11]=O)=[CH:4][CH:3]=1.C(O)(=O)C(C(C(O)=O)O)O.[CH3:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.C([BH3-])#N.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:25]2[CH2:26][CH2:27][CH2:28][C@H:24]2[CH3:23])=[CH:4][CH:3]=1
Reactant: O=C[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1R,2R)-2-(4-bromophenyl)cyclopropanecarbaldehyde (the product of Example 3B, 600 mg, 2.67 mmol) and (R)-2-methylpyrrolidine tartaric acid salt (0.82 g, 3.47 mmol) in ethanol (30 mL) was treated with sodium cyanoborohydride (252 mg 4 mmol). The mixture was stirred at room temperature for two hours. The mixture was quenched with HCl (1N) and then basified to pH=10-12 with NaOH (10%) and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel with 1% to 2% methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CD3OD): δ 0.89 (m, 1H), 0.98 (m, 1H), 1.14 (d, J=6 Hz, 2H), 1.19 (m, 1H), 1.43 (m, 1H), 1.75 (m, 3H), 1.95 (m, 2H), 2.30 (q, J=9 Hz, 1H), 2.37 (m, 1H), 3.14 (dd, J=12 Hz, J=6 Hz, 1H), 3.22 (m, 1H), 7.00 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 294 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:26](=[O:27])[NH:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1
Reactant: CCCN1CCC(O)N(c2nnc(SC)s2)C1=O
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Product: CCCN1CCC(OC(=O)NC2CCCCC2)N(c2nnc(SC)s2)C1=O
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and cyclohexyl isocyanate (3.5 ml; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-(N-cyclohexylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH2:30][CH3:31])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CC
Temperature: 55 °C
Yield: 36 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (210 mg, 0.49 mmol), potassium carbonate (82 mg, 0.59 mmol) and ethyl iodide (44 μl, 0.54 mmol) in DMF was heated at 55° C. for 2 hours. The mixture was allowed to cool to ambient temperature then evaporated. The residue was partitioned between EtOAc (50 mL) and water (15 mL). The organic phase was separated, dried (Na2SO4), filtered and evaporated to give an oil. The oil was purified by flash column chromatography on silica (Si-PPC, pentane:EtOAc, gradient 100:0 to 40:60) to provide the title compound as a yellow solid (80 mg, 36%). LCMS (method B): RT=2.52 min, M+H+=454.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH2:29])(=O)C.B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH2:19]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[N:29]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(COCc1ccccc1)c1ccccc1OCc1ccccc1
Reactant: CC(N)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: c1ccc(COc2ccccc2-c2coc(-c3ccccc3)n2)cc1
Yield: 29.3 %

Procedure:
3.46 g of 2-benzyloxy-1-(2-benzyloxy-phenyl)-ethanone according to step (c) are refluxed with 2.95 g of acetamide and 0.9 ml of boron trifluoride etherate in 100 ml of anhydrous xylene over 20 hours. After the solution obtained has been cooled and washed with water it is dried over sodium sulphate, the solvent is distilled off in vacuo and the residue remaining is chromatographed on silica gel (toluene). In addition to re-isolated educt, 1 g (31%) of the target compound is isolated.