Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:10]([CH2:18][CH2:19][N:20]=3)[C:11]([NH2:17])=[N:12][C:13]=2[C:14]=1[O:15][CH3:16].[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[OH:1][C@H:2]([CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:10]([CH2:18][CH2:19][N:20]=3)[C:11]([NH:17][C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[O:35])=[N:12][C:13]=2[C:14]=1[O:15][CH3:16]
Reactant: O=C(O)c1cccnc1
Reactant: COc1c(OC[C@H](O)CN2CCCCC2)ccc2c1N=C(N)N1CCN=C21
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OC[C@H](O)CN2CCCCC2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Yield: 67.6 %

Procedure:
To a slurry of N-(8-{[(2R)-2-hydroxy-3-(piperidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)amine (0.125 g, 0.34 mmol) and nicotinic acid (0.052 g, 0.42 mmol, 1.3 equiv.) in DMF 3.6 mL) was added PyBOP (0.218 g, 0.42 mmol, 1.3 equiv.) followed by diisopropylethylamine (0.23 mL, 1.34 mmol, 4.0 equiv.). The resulting mixture was stirred at room temperature. After a few hours the mixture turned to a clear solution. The resulting solids were removed by filtration, washed sequentially with DMF, water, then MeOH, and dried at 50° C. under reduced pressure to afford N-(8-{[(2R)-2-hydroxy-3-(piperidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide (0.11 g, 66%): HPLC ret. time 1.00 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.30, 1.44 m, 1H), 1.58-1.71 (m, 2H), 1.72-1.85 (m, 3H), 2.89-3.56 (m, 2H), 3.18 (dd, J=10.1, 13.1 Hz, 1H), 3.25-3.31 (m, 1H), 3.45-3.52 (m, 2H), 4.03 (s, 3H), 4.20-4.29 (m, 4H), 4.38-4.49 (m, 1H), 4.53-4.60 (m, 2H), 7.48 (d, J=9.4 Hz, 1H), 7.85 (dd, J=5.3, 7.9 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 8.82 (br d, J=8.1 Hz, 1H), 8.93 (dd, J=1.5, 5.3 Hz, 1H), 9.47 (d, J=1.5 Hz, 1H); mass spectrum m/z 479 ((M+1)+, 0.4%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.O>[Br:1][C:2]1[C:7]([CH2:8][Br:17])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: Cc1cnc(Cl)cc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Clc1cc(Br)c(CBr)cn1
Temperature: 25 °C

Procedure:
A flask was charged with 4-bromo-2-chloro-5-methylpyridine (513 mg, 2.48 mmol), (PhCO2)2 (32 mg, 0.13 mmol), and NBS (452 mg, 2.54 mmol) then diluted with CCl4 (9 mL). The reaction mixture was heated to reflux for 2 hours and then allowed to cool to room temperature and diluted with CH2Cl2 and H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-20% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd for C6H5Br2ClN 283.9 (M+H+); Found: 283.9 (M+H+).
Reaction SMILES: [OH-:1].[Na+].OO.O.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]1([CH2:33][I:34])[O:18][CH2:17][C@@H:16]([C:19](N2[C@H](C3C=CC=CC=3)COC2=O)=[O:20])[CH2:15]1>O1CCCC1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]1([CH2:33][I:34])[O:18][CH2:17][C@@H:16]([C:19]([OH:20])=[O:1])[CH2:15]1
Reactant: [OH-]
Reactant: O=C1OC[C@@H](c2ccccc2)N1C(=O)[C@@H]1CO[C@@](CI)(c2ccc(F)cc2F)C1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CO[C@@](CI)(c2ccc(F)cc2F)C1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide solution (prepared from 17.7 g of sodium hydroxide and 390 ml of water) was added to a pre-cooled solution of hydrogen peroxide (30 ml), water (65 ml) and tetrahydrofuran (390 ml) at 0-10° C., followed by a solution of (R)-3-((3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl)-4-phenyloxazolidin-2-one compound of formula-6 (130 g) in tetrahydrofuran (390 ml) at 0-10° C. and the reaction mixture was stirred for 30 minutes at 0-10° C. Further temperature of the reaction mixture was raised to 25-30° C. and then stirred for 2 hours at 25-30° C. After completion of the reaction, the reaction mixture was quenched with 10% sodium sulphite solution and the reaction mixture was washed with toluene. The pH of aqueous layer was adjusted to 10.5 using 50% HCl and then washed with dichloromethane. Further pH of aqueous layer was again adjusted to 4.5 using 50% HCl. The aqueous layer was extracted with methyl tertiary butyl ether and distilled off the solvent from methyl tert.butyl ether layer and then co-distilled with cyclohexane. Cyclohexane (190 ml) was added to the obtained compound and stirred for 2 hours at 25-30° C. Filtered the solid, washed with cyclohexane and then dried to get title compound. Yield: 65 g; MR: 80-87° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(NC(C)C)(C)C.CN(C)C=O.[F:24][C:25]([F:29])=[C:26]([F:28])[F:27]>C(OCC)(=O)C.O>[F:24][C:25]([F:29])([S:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)[CH:26]([F:28])[F:27]
Reactant: FC(F)=C(F)F
Reactant: CC(=O)Nc1ccc(S)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(SC(F)(F)C(F)F)cc1
Yield: 87.3 %

Procedure:
A mixture of 25 g (0.15 mole) of 4-acetamidothiophenol and 15 g (0.15 mole) of diisopropylamine in 80 of dimethylformamide was treated with 15 g (0.15 mole) of tetrafluoroethylene in a bomb. The temperature was slowly raised from -44° C. to 25° C. The reaction mixture was then poured into water and the solid product was isolated by filtration. The solid was dissolved in ethyl acetate and the resulting solution was dried over anhydrous magnesium sulfate, filtered, and concentrated. The solid residue was triturated with petroleum ether and filtered to give 35 g (87.5% yield) of p-(1,1,2,2-tetrafluoroethylthio)acetanilide (XI); m.p. 133.5°-135° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:42]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:42])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(N(C)Cc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate.
Reaction SMILES: [C:1]([O:11]C)(=O)[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH3:13][NH2:14].CO>>[OH:3][C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([NH:14][CH3:13])=[O:11]
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
Methyl (S)-(+)-mandelate 36 (4.60 g, 27.7 mmol, 1.0 eq) was added to a 2M solution of methylamine in methanol, (70 mL, 140 mmol, 5.05 eq) and the mixture was stirred at rt for 24 h. The mixture was concentrated under reduced pressure to a semi-solid. Residual methanol was co-evaporated with toluene (2×50 mL) followed by 1:1 toluene/heptanes (50 mL) to give a white crystalline solid. The solid was triturated with heptanes (50 mL), filtered and dried to give 4.35 g (95%) of 37 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(OC)(C)(C)C>[C:18]([O:17][C:16](=[O:22])[NH:15][O:14][S:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:12])=[O:11])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Reaction time: 2 h

Procedure:
2,4,6-trimethylbenzenesulfonyl chloride (5 g, 0.022 mol) was added to a solution of methyl tertiary-butyl ether (50 mL) under nitrogen atmosphere at 0° C., followed by the addition of tert-butyl hydroxycarbamate (3.04 g, 0.22 mol) at 0° C. Next, triethylamine (3.24 mL, 0.023 mol) was added drop wise to the reaction mixture, which was then it was allowed to stir for 2 h. The reaction product was filtered through sintered funnel and the filtrate was concentrated under vacuum up to ¾ volume. Hexane (50 mL) was added to the concentrated filtrate, which was then stirred for 20 min wherein a precipitate formed. The participate was collected by filtration and the solid dried to afford tert-butyl(mesitylsulfonyl)oxycarbamate. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.31 (s, 1H), 2.38 (s, 9H). MS (M+1): 316.3.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.C1C=CC(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)=CC=1.[CH2:30]1[CH2:40][CH2:39][N:38]2[C:33](=[N:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31]1>CCOC(C)=O>[OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[N:27]([CH2:30][C:40]1[CH:39]=[N:38][CH:37]=[C:36]2[C:35]=1[N:34]=[CH:33][CH:32]=[CH:31]2)=[N+:28]=[N-:29]
Reactant: C1CCC2=NCCCN2CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: OCc1cncc2cccnc12
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1cncc2cccnc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.93 g (5.8 mmol) 8-hydroxymethyl-1,6-napthyridine in 20 mL TBF was added 1.5 mL (7 mmol) DPPA and 1.2 mL (6.7 mmol) DBU. The reaction mixture was allowed to stir at room temperature 18 hours, then another 0.3 mL DPPA and 0.25 mL DBU were added and the reaction mixture heated to 50° C. for 8 hours then cooled to room temperature then another 0.3 mL DPPA and 0.25 mL DBU were added and the reaction mixture was allowed to stir 18 more hours at room temperature. The resulting solution was then diluted with 200 L EtOAc, washed with saturated NaHCO3 solution, and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (40×120 mm silica gel, linear gradient 2-15% MeOH:CH2Cl2) yielded 8-hydroxymethyl-1,6-napthyridine and 8-azidomethyl-1,6-napthyridine. 1H NMR (CDCl3, 400 MHz) δ 9.30 (s, 1H); 9.16 (dd, 1H, J=4.3 and 1.8 Hz); 8.78 (s, 1H); 8.35 (dd, 1H, J=8.3 and 1.74 Hz); 7.61 (dd, 1H, J=8.3 and 4.3 Hz); 5.00 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]2[S:15]([CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])=[O:16])=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH:32]=[C:31]([CH2:33][NH:34][CH3:35])[C:30]([CH3:36])=[N:29]1.C([BH3-])#N.[Na+]>CN(C=O)C.C(O)(=O)C>[CH3:27][N:28]1[CH:32]=[C:31]([CH2:33][N:34]([CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9]([S:15]([CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=3[F:26])=[O:16])=[N:10][CH:11]=2)[CH3:35])[C:30]([CH3:36])=[N:29]1
Reactant: CNCc1cn(C)nc1C
Reactant: O=Cc1cnc(S(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1nn(C)cc1CN(C)Cc1cnc(S(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
A solution of 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfinyl)-1H-imidazole-5-carbaldehyde (33) (39 mg, 0.10 mmol), 1-(1,3-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine (15 mg, 0.11 mmol), sodium cyanoborohydride (30 mg, 0.11 mmol) and DMF/acetic acid (10/1, 1 mL) was stirred at room temperature overnight. The reaction mixture was directly loaded on to reverse phase preparative HPLC column and purified to yield 1-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfinyl)-1H-imidazol-5-yl)methyl)-N-methylmethanamine (501). 1H NMR (400 MHz, CDCl3) δ: 7.63 (s, 1H), 7.52 (s, 1H), 7.45-7.36 (m, 1H), 7.24-7.09 (m, 4H), 6.90-6.85 (m, 1H), 4.87 (d, J=13.0, 1H), 4.58 (d, J=13.0, 1H), 4.27 (d, J=14.5, 1H), 4.11 (s, 1H), 3.99 (d, J=13.2, 1H), 3.90-3.79 (m, 4H), 2.57 (s, 3H), 2.18 (s, 3H). LC-MS ESI m/z; found 506.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3([C:23]([O:25]C)=[O:24])[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:27][C:28]([NH2:30])=[NH:29])=[N:4][CH:3]=1.[OH-].[Na+].Cl>CO>[ClH:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3([C:23]([OH:25])=[O:24])[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:27][C:28]([NH2:30])=[NH:29])=[N:4][CH:3]=1
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)(C(=O)O)CC1
Yield: 31.8 %

Procedure:
A solution of methyl 4-[({4-chloro-1-guanidino-7-isoquinolinyl}sulphonyl)amino]-1-methyl-4-piperidinecarboxylate (100 mg, 0.22 mmol) in aqueous NaOH (2 ml, 2M, 4 mmol) and MeOH (5 ml) was stirred at 60° C. for 42 h. The cooled solution was neutralised using 2M HCl, and the mixture concentrated in vacuo, until precipitation occurred. The solid was filtered, dried and dissolved in concentrated HCl, and the solution evaporated in vacuo. The resulting solid was triturated with Et2O, then i-PrOH, and dried under vacuum, to give 4-[({4-chloro-1-guanidino-7-isoquinolinyl}sulphonyl)amino]-1-methyl-4-piperidinecarboxylic acid hydrochloride (18 mg, 0.035 mmol).
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[OH:25][C@H:26]1[CH2:30][NH:29][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27]1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1.ClCCl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([N:29]4[CH2:30][C@H:26]([OH:25])[CH2:27][C@H:28]4[C:31]([O:33][CH3:34])=[O:32])[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Temperature: 120 °C

Procedure:
500 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 284.19 mg methyl (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylate and 691.65 μl diisopropylethylamine are placed in 8 ml dioxane, heated to 120° C. in the microwave for 0.3 hours. Then the reaction mixture is combined with water and dichloromethane and extracted. The organic phase is separated off using a phase separation cartridge and evaporated to dryness. The diastereomers are separated by preparative HPLC (method B). 200 mg of Diastereomer 1 (Example 125) and 160 mg of Diastereomer 2 (Example 126) are obtained as powders. Analytical HPLC-MS (method A): Diastereomer 1, RT=2.51 min, Diastereomer 2, RT=2.57 min.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:13][O:14][C:15]1[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=1[CH:17]=[N+:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:13][O:14][C:15]1[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=1[CH:17]([C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:10][CH:9]=1)[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: COc1ccccc1C=[N+]1CCOCC1
Reactant: c1ccc(-n2cccc2)cc1
Agent: [Cl-]
Product: COc1ccccc1C(c1cccn1-c1ccccc1)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-phenyl-1H-pyrrole and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([N+:12]([O-])=O)=[C:4]([CH3:15])[N:3]=1.CS(O)(=O)=O.[H][H]>[Pd].C.CO>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[C:5]([NH2:12])=[C:4]([CH3:15])[N:3]=1
Reactant: [H][H]
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Product: Cc1nc(N)c(N)c(C)c1N

Procedure:
A 500 ml Parr Bottle was charged with 2-amino-4,6-dimethyl-3,5-dinitropyridine (21.2 g, 0.10 mole), 200 ml methanol, methanesulfonic acid (19.2 g, 0.20 mole), and 20. g 5% Pd/charcoal catalyst. The mixture was subjected to hydrogenation at ambient temperature with an initial hydrogen pressure of 5.7 psig. When no further uptake of hydrogen was observed, the mixture was filtered free of catalyst under a nitrogen atmosphere, and methanol removed under vacuum. The bismethanesulfonate salt of 2,3,5-triamino-4,6-dimethylpyridine so obtained was purified by slurrying with dry isopropyl alcohol, filtering under nitrogen, and vacuum drying over P2O5 at 80° - 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][O:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][O:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCCOC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2CCCOC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
712 mg (purity 85%, 1.02 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoyl}amino)benzoate (mixture of racemic diastereomers) were hydrolysed with TFA according to General Method 2. Yield: 209 mg (38% of theory)
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I:9]I.CO.S([O-])([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[N:7]=[C:6]([I:9])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)nc1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1ccc(F)nc1I
Temperature: 25 °C
Reaction time: 120 h
Yield: 19 %

Procedure:
6-Fluoro-3-hydroxypyridine (870 mg) and iodine (9.76 g) were dissolved in a mixed solvent composed of methanol (20 ml) and water (10 ml) to prepare a solution which was then stirred at room temperature for 120 hr. Thereafter, sodium sulfite was added until the solution became transparent. Methanol in the reaction solution was removed under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 6-fluoro-2-iodo-pyridin-3-ol (350 mg, yield 19%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:12]([CH3:16])([CH2:13]2)[CH2:11][CH2:10][C:9](=[O:17])[CH:8]=3)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[Br:23]Br>C(Cl)Cl.CCOC(C)=O>[Br:23][C:8]1[C:9](=[O:17])[CH2:10][CH2:11][C:12]2([CH3:16])[C:7]=1[C:6]1[C:14](=[CH:15][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:13]2
Reactant: BrBr
Reactant: COc1ccc2c(c1)CC1(C)CCC(=O)C=C21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(c1)CC1(C)CCC(=O)C(Br)=C21
Temperature: 25 °C
Reaction time: 22 h
Yield: 46.5 %

Procedure:
A mixture of 7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (32 mg, 0.14 mmol) and NaHCO3 (60 mg, 0.7 mmol) in CH2Cl2 (0.5 ml) was treated with bromine (0.008 mL, 0.154 mmol), and the resulting mixture was stirred at room temperature for 22 hours. The mixture was diluted with EtOAc (8 ml), washed with dilute aqueous Na2S2O3 (4 mL) and brine (4 ml), dried over MgSO4, filtered, and evaporated under vacuum to a yellow oil (43 mg). This material was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing twice with CH2Cl2, to afford 4-bromo-7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (20 mg) as a gum. The product was contaminated with a trace of 4,6-dibromo-7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one.
Reaction SMILES: [NH2:1][C:2](=[O:17])[CH:3]([NH:9]C(=O)OC(C)(C)C)[CH2:4][C:5]([F:8])([F:7])[F:6].[ClH:18]>O1CCOCC1>[ClH:18].[NH2:9][CH:3]([CH2:4][C:5]([F:8])([F:7])[F:6])[C:2]([NH2:1])=[O:17]
Reactant: CC(C)(C)OC(=O)NC(CC(F)(F)F)C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C(N)CC(F)(F)F

Procedure:
A solution of the solid tert-butyl 1-amino-4,4,4-trifluoro-1-oxobutan-2-ylcarbamate in dioxane (4 mL) and aq. 6N HCl (6 mL) was stirred at room temperature for 1 h. It was then concentrated in vacuo to give 2-amino-4,4,4-trifluorobutanamide hydrochloride as a solid (135 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:48])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:48])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([N:43]3[CH2:44][CH2:45][CH2:46][CH2:47]3)[CH:38]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K63) (275 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow amorphous substance (379 mg, 82%).