Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:10][C:11]1[CH:16]=[C:15]([O:9][C:5]2[C:6]([CH3:8])=[N:7][C:2]([I:1])=[CH:3][CH:4]=2)[N:14]=[CH:13][N:12]=1
Reactant: Cc1nc(I)ccc1O
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(I)ccc1Oc1cc(Cl)ncn1
Temperature: 110 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
6-Iodo-2-methylpyridin-3-ol (2.00 g, 8.51 mmol) and 4,6-dichloropyrimidine (5.00 g, 33.6 mmol) were dissolved in DMA (40 mL) and sonicated and sparged with Ar for 10 min. K2CO3 (2.00 g, 14.5 mmol) was added and the reaction mixture was stirred at 110° C. for 16 h. The mixture was partitioned between water (260 mL) and EtOAc (100 mL). The solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3×25 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 4-chloro-6-((6-iodo-2-methylpyridin-3-yl)oxy)pyrimidine (2.8 g, 95%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.63 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z: 348.0 (M+H+).
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:14][C@H:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:12]2)=[CH:7][CH:6]=1>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:10]1[CH:9]=[C:8]([C@H:11]2[CH2:12][C@H:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:14]2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COC(=O)C[C@H]1C[C@H](c2ccc(OC)cc2)C1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)C[C@H]1C[C@H](c2ccc(OC)c(I)c2)C1
Reaction time: 4 h

Procedure:
Silver sulfate (0.149 g, 0.478 mmol) and iodine (0.025 mL, 0.478 mmol) were added successively to a solution of methyl [trans-3-(4-methoxyphenyl)cyclobutyl]acetate (0.1119 g, 0.478 mmol) in MeOH (2.4 mL) at 25° C. and the reaction was stirred vigorously for 4 h. After this time the reaction mixture was filtered through a plug of Celite®. The filtrate was diluted with EtOAc (50 mL), washed with water (2×10 mL), aq. Na2SO3 (2×10 mL), and brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 2394 mL) to afford methyl [trans-3-(3-iodo-4-methoxyphenyl)cyclobutyl]acetate, as a colorless oil. Rf=0.45 (20% EtOAc/hexanes), LCMS calc.=383.01. found=382.92 (M+Na). 1H NMR (500 MHz, CDCl3): δ 7.64 (d, J=2.2 Hz, 1H); 7.16 (dd, J=8.4, 2.2 Hz, 1H); 6.76 (d, J=8.4 Hz, 1H); 3.85 (s, 3H); 3.68 (s, 3H); 3.56-3.46 (m, 1H); 2.74-2.66 (m, 1H); 2.60 (d, J=7.9 Hz, 2H); 2.35-2.27 (m, 2H); 2.17-2.10 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:43][C@@H:42]([CH3:44])[N:41]([CH:45]6[CH2:48][O:47][CH2:46]6)[CH2:40][C@@H:39]5[CH3:49])=[CH:34][N:33]=4)[C:28](=[O:50])[N:27]([CH3:51])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:43][C@@H:42]([CH3:44])[N:41]([CH:45]6[CH2:48][O:47][CH2:46]6)[CH2:40][C@@H:39]5[CH3:49])=[CH:34][N:33]=4)[C:28](=[O:50])[N:27]([CH3:51])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
A mixture of 110a (100 mg, 0.15 mmol) and NaBH4 (20 mg, 0.45 mmol) in MeOH (30 mL) was stirred at 30° C. for 2 h. The mixture was quenched with water and extracted with EtOAc (10 mL×3). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 110 (80 mg, 80%). MS: [M+H]+ 695.3. 1H NMR (500 MHz, CDCl3) δ 8.72 (d, J=2, 1H), 8.67 (d, J=5, 1H), 8.35 (d, J=2.5, 1H), 8.05 (d, J=3, 1H), 7.88 (s, 1H), 7.68 (d, J=2.5, 1H), 7.58-7.55 (m, 3H), 7.38-7.36 (m, 1H), 6.82 (d, J=8.5, 1H), 4.78-4.71 (m, 2H), 4.67-4.61 (m, 2H), 4.50 (s, 2H), 4.07 (t, J=6, 1H), 3.78-3.74 (m, 4H), 3.22-3.20 (m, 1H), 2.92 (d, J=3, 1H), 2.77-2.71 (m, 2H), 2.51-2.48 (m, 1H), 1.20-1.95 (m, 1H), 1.45 (s, 9H), 0.93-0.90 (m, 6H)
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:40][CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:12](=[O:39])[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18](=[O:30])[NH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:10][C@@H:11]([CH2:40][CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:12]([NH:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:18]([NH:19][CH2:20][CH2:21][NH:22][C:23]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:29])=[O:30])[NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[O:39]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CCCNC(=O)[C@H](CCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CCCNC(=O)[C@@H](N)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C

Procedure:
355 mg (0.5 mmol) of the compound from Example 267A are dissolved in 17 ml of ethanol, and 36 mg (0.03 mmol) of Pd/C (10%) are added. The mixture is hydrogenated under atmospheric pressure overnight and, after filtration through celite, the filtrate is concentrated in vacuo. The solid obtained in this way is reacted further without purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[C:16]=4[C:15](=[O:26])[N:14]([CH3:27])[CH2:13][C:12]=23)[N:4]=1.[CH2:28]([NH:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]>CN(C)C=O>[CH2:28]([N:31]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[C:16]=4[C:15](=[O:26])[N:14]([CH3:27])[CH2:13][C:12]=23)[N:4]=1)[CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(C(F)(F)F)c2C1=O
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c-3cccc2C(F)(F)F)no1
Yield: 95.9 %

Procedure:
1.19 g (3 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 5 hours with 1.02 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with water. By drying the organic phase over magnesium sulfate and evaporating the solvent there were obtained 1.33 g (96%) of 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 216°-218°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:10]([NH:11][C:12](=S)[NH2:13])=[C:9]([C:15]([NH2:17])=[O:16])[N:8]=[CH:7]1.OO>[OH-].[Na+].[O-][W]([O-])(=O)=O.[Na+].[Na+]>[OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:7]=[N:8][C:9]2[C:15](=[O:16])[NH:17][C:12]([NH2:13])=[N:11][C:10]1=2
Reactant: NC(=O)c1ncn(COCCO)c1NC(N)=S
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Reaction time: 0.25 h
Yield: 59 %

Procedure:
1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (2.59 g, 10.0 mM) and sodium tungstate (0.05 g) were dissolved in 6N sodium hydroxide (20 ml) at 5° C. 35% hydrogen peroxide (4.0 ml, 44 mM) was added dropwise at 5°-15° C. in the course of 15 minutes. After stirring for 15 minutes at 0°-5° C. HPLC indicated 59% yield of the title compound. The pH-value of the reaction mixture was adjusted to 5.5 with 25% aqueous acetic acid. The resulting product was filtered off, washed with water and dried which gave 1.13 g (50%) of the title compound as a white powder. HPLC indicated a purity of about 97%. The product had the same physical data as the product of example 5.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:2].Cl[CH2:11][CH2:12][C:13]12[CH2:20][CH2:19][CH2:18][N:17]1[CH2:16][CH2:15][CH2:14]2>>[N:17]12[CH2:18][CH2:19][CH2:20][C:13]1([CH2:12][CH2:11][N:3]([CH:1]=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:14][CH2:15][CH2:16]2
Reactant: O=CNc1ccccc1
Reactant: ClCCC12CCCN1CCC2
Product: O=CN(CCC12CCCN1CCC2)c1ccccc1

Procedure:
The procedures described in Example 2 were repeated except that formanilide (1.80 g, 14.9 mmol) and 5-(2-chloroethyl)-1-azabicyclo[3.3.0]octane (hydrochloride, 3.43 g, 16.3 mmol ) were employed. In this case, the desired compound was obtained as a pale yellow liquid (3.39 g, 88.1 %).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:17]2[N:25]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:5]1.[I-:36].[Na+]>C(C(C)=O)C>[I:36][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:17]2[N:25]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:5]1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCl)c2cc1OC
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Yield: 61.5 %

Procedure:
A solution of 2-[1-(2-chloroethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.331 g; 649 μmol), described in example 1, and sodium iodide (0.195 g; 1.298 mmol) in methyl ethyl ketone (5 ml) is placed in a 10 ml round-bottomed flask. The reaction mixture is brought to reflux for 16 hours. After evaporation, the product is taken up in a mixture of water (15 ml) and ethyl acetate (15 ml). After separation by settling out and extraction with ethyl acetate (2×15 ml), the organic extracts are combined, dried over magnesium sulfate, and then evaporated under reduced pressure. The evaporation residue is chromatographed on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (50/50). The fractions containing the expected compound are combined and evaporated, giving 2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.24 g; 69%), the characteristics of which are as follows:
Reaction SMILES: O[C:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][CH2:4][C:5]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:6]>CO.[Pd]>[CH3:6][C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH2:4][CH2:3][CH:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(CCC(O)(c1ccccc1)c1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Product: CC(CCC(c1ccccc1)c1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 85.2 %

Procedure:
A solution of the product from Example 1 (2.00 g, 4.71 mmol) in 100 mL of methanol was shaken with 20% Pd/C (0.25 g) on a Parr apparatus under a H2 atmosphere (50 psi) for 21 hours. The reaction mixture was filtered and the filtrate concentrated to give the title compound (1.64 g, 85%) as a white foam.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[C:7]2[C:8](=[C:13]([CH3:22])[N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1>C1(C)C(C)=CC=CC=1>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[C:7]2[C:8](=[C:13]([CH3:22])[N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: NCCO
Reactant: Cc1cc(Cl)c2nn(-c3ccccc3)c(C)c2n1
Solvent: Cc1ccccc1C
Product: Cc1cc(NCCO)c2nn(-c3ccccc3)c(C)c2n1

Procedure:
A mixture of ethanolamine (1.0 ml) and 7-chloro-3,5-dimethyl-2-phenylpyrazolo[4,3-b]pyridine (0.080 g) in dry xylene (5 ml) was heated under reflux for 48 h. After cooling, the resulting brown oil solidified. The solvent was decanted off and the solid washed several times with xylene. The brown solid was dissolved in aqueous methanol and the pH adjusted to pH 8-9 with 10% sodium carbonate solution. The resulting solid was filtered off, dried and recrystallised from chloroform/pentane to give the title compound as a beige solid (0.029 g), m.p. 159°-161° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N:18][CH:19]=[CH:20][CH:21]=2.COC1C=C(S(Cl)(=O)=O)C=CC=1C(O)=O.[CH3:38][NH:39][CH3:40]>>[ClH:13].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([S:10]([N:39]([CH3:40])[CH3:38])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N:18][CH:19]=[CH:20][CH:21]=2
Reactant: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2ncccc2[nH]1
Reactant: CNC
Agent: COc1cc(S(=O)(=O)Cl)ccc1C(=O)O
Agent: Cl
Product: COc1cc(S(=O)(=O)N(C)C)ccc1-c1nc2ncccc2[nH]1
Temperature: 0 °C

Procedure:
The crude 2-(2'-methoxy-4'-chlorosulfonyl-phenyl)-imidazo[4,5-b]pyridine hydrochloride prepared from 2.5 gm of 2-methoxy-4-chlorosulfonyl-benzoic acid according to Example C was added to 150 ml of a saturated aqueous dimethylamine solution at 10° C., under stirring, and a light-colored precipitate formed slowly. After stirring for 20 hours at ambient temperature, 200 ml of ice water were added. The precipitate was dried and then taken up in 60 ml of methanol, and 10 ml of methanolic hydrochloric acid were added. After filtering over active charcoal, the solvent was eliminated, and the residue remaining was digested with acetone and ether, subjected to suction filtration, and washed with ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH2:24])=[CH:20][CH:21]=2)[CH:16]=[N:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:14]([CH3:13])[N:15]=[CH:16]3)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Reactant: Cn1ncc2cc(CN)ccc21
Product: Cn1ncc2cc(CNS(=O)(=O)c3ccc(Br)cc3Cl)ccc21

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from 4-bromo-2-chlorobenzene-1-sulfonyl chloride and (1-methyl-1H-indazol-5-yl)methanamine.
Reaction SMILES: C(C1C=C(C)C(S(F)(F)[F:13])=C(C)C=1)(C)(C)C.[C:17]([N:34]1[CH2:38][C@H:37]([F:39])[CH2:36][C@H:35]1[C:40](O)=[O:41])([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18]>ClCCl>[C:17]([N:34]1[CH2:38][C@H:37]([F:39])[CH2:36][C@H:35]1[C:40]([F:13])=[O:41])([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1S(F)(F)F
Reactant: O=C(O)[C@@H]1C[C@@H](F)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: O=C(F)[C@@H]1C[C@@H](F)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of 4-(tert-butyl)-2,6-dimethylphenylsulfur trifluoride (10.5 mmol) in 5 ml of dichloromethane was added slowly to a stirred solution of (2S,4R)—N-Fmoc-4-fluoropyrrolidine-2-carboxylic acid (7 mmol) in 15 mL of dichloromethane in a fluoropolymer (PFA) reactor cooled on an ice bath. After complete addition, the ice bath was removed and stirred at room temperature for 0.5 h. 19F NMR analysis of the reaction mixture showed that (2S,4R)—N-Fmoc-4-fluoropyrrolidine-2-carbonyl fluoride (Ib) was produced in 97% yield. All the volatiles were removed at reduced pressure, and dichloromethane (2 ml) was added to the residue, followed by the addition of pentane (30 ml). After stirring well, a supernatant liquid was removed and the residue was washed with pentane (25 ml×2). Finally the product (Ib) (1.75 g, 70% yield) was obtained as white powder by dissolving the solid in dichloromethane and precipitating with pentane. 19F-NMR (CDCl3) (a 6:4 mixture of two rotamers) δ 29.69 (s, 0.6 F, COF), 29.39 (s, 0.6 F, COF), −177.05 (m, 0.6 F, CF), −177.99 (m, 0.4 F, CF): 1H-NMR (CDCl3) 8 (as a mixture of rotamers) 2.0-2.9 (m, 2H), 3.4-4.8 (m, 6H), 5.05-5.5 (m, 1H), 7.2-7.9 (m, 8H): 13C-NMR (CDCl3) 8 (as a mixture of two rotamers) δ0.40 (d, J=179.9 Hz, CF), 91.39 (d, J=180.6 Hz, CF), 154.16 (CON), 154.85 (CON), 161.49 (d, J=367.8 Hz, COF): High Resolution Mass/ESI-APCI method (solvent; methanol); (M-F+OCH3+Na)+392.1272 [calcd 392.1269 for (C21H20FNO4+Na)].
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:40]([CH2:41][CH3:42])=[CH:39][N:38]=[C:37]([CH3:43])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:40]([CH2:41][CH3:42])=[CH:39][N:38]=[C:37]([CH3:43])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K19) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown solid (260 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:24][CH2:25][N:26]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]=3[CH:10]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: CN(C)C(=O)C1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: CN(C)C(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (General Procedure D-2) and piperidine-4-carboxylic acid dimethylamide (Example 42) using General Procedure B-3 yielded 1-(2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid dimethylamide.
Reaction SMILES: [OH-].[K+].[O-2].[Al+3].[O-2].[O-2].[Al+3].C(S([CH2:18][C@@H:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)=O)C1C=CC=CC=1.BrC(Br)(F)F>CO.C(O)CCC>[C:21]1([CH2:20][C@H:19]([NH2:27])/[CH:18]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1
Agent: FC(F)(Br)Br
Agent: [Al+3]
Agent: [K+]
Solvent: CCCCO
Solvent: CO
Product: N[C@H](/C=C/c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
552.7 mg (9.85 mmol) of potassium hydroxide were dissolved in methanol, adsorbed onto 1.1 g of neutral aluminium oxide and then dried under high vacuum. To a solution of 240 mg (0.82 mmol) of (2S)-1-(benzylsulphonyl)-3-phenylpropan-2-amine and 1.56 g of the potassium hydroxide on aluminium oxide thus prepared in 6.2 ml of n-butanol were added dropwise, at 5-10° C., 307 μl (3.3 mmol) of dibromodifluoromethane. The reaction mixture was stirred at RT for 2 h, then filtered through Celite, and the residue was washed thoroughly with dichloromethane. The filtrate was concentrated and the resulting residue was dried under reduced pressure. The crude product thus obtained was purified by means of preparative HPLC. 98 mg (35% of theory) of the title compound were obtained with an E/Z diastereomer ratio of 4:1.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7](F)[N:6]1[O:13][CH:14]([F:16])[F:15]>C(OCC)C>[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([N:2]([CH3:3])[CH3:1])[N:6]1[O:13][CH:14]([F:16])[F:15]
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Reactant: CNC
Solvent: CCOCC
Product: CN(C)C1=NC(Cl)=NC(N)N1OC(F)F
Reaction time: 8 h

Procedure:
4.2 g (0.093 mol) of dimethylamine were passed into a solution of 10 g (0.047 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine in 150 ml of diethyl ether at 0° C. in the course of 20 minutes, while stirring. Stirring was continued for one hour at 0° C. and overnight at 22° C. Washing with water, drying and evaporating down gave 9.8 g (87.8% of theory) of the title compound of melting point 130°-133° C. (decomposition).
Reaction SMILES: [C:1]([C:3]([C:16](=[O:29])[N:17]([CH3:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=[CH:4][NH:5][C:6](=[NH:15])[N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]1=[O:14])#[N:2].O.[OH-].[Na+]>C(O)=O.ClCCl>[CH3:28][N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1)[C:16]([C:3]1[C:1]([NH2:2])=[N:15][C:6]([N:7]2[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]2=[O:14])=[N:5][CH:4]=1)=[O:29]
Reactant: CN(C(=O)C(C#N)=CNC(=N)N1CC(C)(C)NC1=O)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: ClCCl
Product: CN(C(=O)c1cnc(N2CC(C)(C)NC2=O)nc1N)c1cccc(C(F)(F)F)c1
Yield: 56.9 %

Procedure:
A solution of 1.634 g (4 mmol) of 1-cyano-1-[N-methyl-N-(3-trifluoromethylphenyl)carbamoyl]-2-[imino(4,4-dimethyl-2-oxo-1-imidazolidinyl)methylamino]ethene (compound IV) in 3 ml of formic acid (98-100% strength) was heated at 50° C. for 2 hours. The formic acid was then stripped off in vacuo, the residue was taken up in dichloromethane, 20 ml of water were added, and the pH was adjusted to between 9 and 10 with dilute sodium hydroxide solution. The organic phase was separated off. The aqueous phase was extracted twice more with dichloromethane. The combined dichloromethane extracts were washed successively with 2 ml of 0.5N NaOH and twice with water, dried with MgSO4 and evaporated in vacuo. The remaining solid residue was mixed with ether/heptane 1:1 and filtered off with suction. After drying (compare Example 13), 0.93 g (=56.9% yield) of pure 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-methyl-N-(3-trifluoromethylphenyl) amide was obtained, melting point 210°-211° C.; TLC in CH2Cl2 /C2 H5OH=10:1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.Cl.[C:11]([O:15][C:16](=[O:19])[CH2:17][NH2:18])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C.O>[C:8]([C:4]1[N:3]=[C:2]([NH:18][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:19])[N:7]=[CH:6][CH:5]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1ccnc(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNc1nccc(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
2-Chloro-6-cyanopyrimidine (2.09 g, 15.0 mmol), glycine tert-butyl ester hydrochloride salt (2.52 g, 15.0 mmol) and triethylamine (2.38 ml, 17.0 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.07 g, 45%) as pale yellow crystals.