Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]3)[C:9]2([C:12]([F:15])([F:14])[F:13])[CH2:11][O:10]2)=[C:4]([F:28])[C:3]=1[O:29][CH3:30].[CH2:31]([SH:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([CH3:27])=[N:22]3)[C:9]([CH2:11][S:33][CH2:31][CH3:32])([C:12]([F:13])([F:15])[F:14])[OH:10])=[C:4]([F:28])[C:3]=1[O:29][CH3:30]
Reactant: CCS
Reactant: COc1c(Cl)ccc(C(Nc2cccc3nc(C)ccc23)C2(C(F)(F)F)CO2)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(Cl)c(OC)c1F)C(F)(F)F

Procedure:
Analogously to example 45 100 mg (0.25 mmol) {[4-chloro-2-fluoro-3-methoxyphenyl][2-(trifluoromethyl)oxiranyl]methyl}-(2-methylquinolin-5-yl)amine (example 13) are reacted with 0.24 ml of the 1 M ethanthiol solution under the presence of 148 mg Caesium carbonate in DMF. The typical work up after 2 hours yields 54 mg of the title compound after preparative thin layer chromatography on silica gel (aceton in hexane 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:19][C:18]1[N:5]([C:4]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=2[O:2][CH3:1])[C:14]([CH3:16])=[CH:13][CH:17]=1
Reactant: CC(=O)CCC(C)=O
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc([N+](=O)[O-])ccc1-n1c(C)ccc1C
Yield: 99.2 %

Procedure:
A stirred mixture of 29.0 g (0.17 mole) of 2-methoxy-4-nitroaniline, 18.7 g (0.16 mole) of acetonylacetone and 0.5 g (0.0026 mole) of p-toluenesulfonic acid in 300 ml of toluene was heated at reflux for two hours. A Dean-Stark trap was used to collect a calculated volume of water. The reaction mixture was cooled then poured into 250 ml of ice water. To the mixture was added 100 ml 2N hydrochloric acid. The organic phase was separated and washed in succession with 100 ml of 2N hydrochloric acid, 100 ml of saturated aqueous sodium chloride, 100 ml of 5% aqueous sodium bicarbonate and 100 ml of saturated aqueous sodium chloride. The washed organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under reduced pressure to yield 39.1 g of 2,5-dimethyl-1-(2-methoxy-4-nitrophenyl)pyrrole.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH2:2]1.[NH3:11]>C(O)C>[NH2:11][CH:2]([OH:1])[CH2:3][CH2:4][O:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1
Reactant: N
Reactant: c1csc(OCC2CO2)n1
Solvent: CCO
Product: NC(O)CCOc1nccs1

Procedure:
This example illustrates methods according to the invention of converting the compounds of formula II, of the invention, into the compounds of formula I of the invention. In this example, 300 mg. of 1,2-epoxy-3-(thiazol-2-oxy)-propane is dissolved in 5 ml. of ethanol saturated with ammonia and left at room temperature for 20 hours. The reaction mixture is then evaporated to remove all residual solvent, and the residue is purified by thin-layer chromatography on preparative silica plate using a developing system of 1 percent triethylamine, 1.5 percent methanol and the remainder ethyl acetate to yield 1-amino-3-(thiazol-2-oxy)-propanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:31])[C:11](=[O:30])[CH:12]=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][C@@H:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])=[O:16])=[C:4]([F:32])[CH:3]=1.Cl>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:31])[C:11](=[O:30])[CH:12]=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][C@@H:20]([OH:22])[CH3:21])=[O:16])=[C:4]([F:32])[CH:3]=1
Reactant: C[C@@H](CONC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](O)CONC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.7 %

Procedure:
To a solution of (S)-2-(4-bromo-2-fluorophenylamino)-N-(2-(tert-butyldimethylsilyloxy)propoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.074 g, 0.14 mmol) in THF (1.50 mL) was added 1 M aqueous HCl (1.4 ml, 1.4 mmol). The reaction was stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 (3×) and saturated aqueous NaCl. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to yield a crude white solid. Purification of the crude product by trituration with Et2O and isolation of the resulting solid provided (S)-2-(4-bromo-2-fluorophenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.030 g; 52% over two steps) as a white solid. MS ESI (+) m/z 414, 416 (M+) Br pattern detected; 1H NMR (400 MHz, CD3OD) δ 7.65 (d, 1H), 7.42 (dd, 1H), 7.28 (m, 1H), 6.81 (t, 1H), 6.28 (d, 1H), 3.88 (m, 1H), 3.70 (dd, 1H), 3.58 (dd, 1H), 3.38 (s, 3H), 1.11 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[N:10]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)CBr
Reactant: COc1cc2c(-c3ccnc(Br)c3)n[nH]c(=O)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1nc(-c2ccnc(Br)c2)c2cc(OC)c(OC)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-4-(6,7-dimethoxyphthalazin-1(2H)-on-4-yl)pyridine (362 mg) in dimethylformamide (2 ml) is added sodium hydride (48 mg, 62.4% in oil,) with ice-cooling under nitrogen atmosphere, and the mixture is stirred at room temperature for 30 minutes. To the mixture is methyl bromoacetate (0.11 ml) under ice-cooling, and the mixture is stirred for 15 minutes. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed, dried, and concentrated to give 2-bromo-4-(6,7-dimethoxy-2-methoxycarbonylmethylphthalazin-1(2H)-on-4-yl)pyridine (390 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[N:20][C:19]=1[Cl:27]>CN(C=O)C>[Cl:27][C:19]1[N:20]=[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]2[C:18]=1[CH2:17][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1nc2ccccn2c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(Cl)nc3ccccn23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (600 mg, 4.2 mmol) was dissolved in anhydrous DMF (20 mL), and then potassium carbonate (1.75 g, 12.7 mmol) and 3-(bromomethyl)-2-chloroimidazo[1,2-a]pyridine (5.5 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 0-12% DCM/MeOH to afford the title compound (165 mg, 15% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 4.85 (s, 2H), 6.03 (bs, 1H), 7.10 (t, J=6.7 Hz, 1H), 7.39 (t, J=7.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 8.59 (d, J=6.8 Hz, 1H); LRMS (ES+) m/z 307 (85%, M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]12[CH2:14][CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([C:15](OC)=[O:16])[CH2:8]2.[Li].O>C(OCC)C>[N:7]12[CH2:14][CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([CH2:15][OH:16])[CH2:8]2
Reactant: COC(=O)C1CN2CCC1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCC1CN2CCC1CC2
Reaction time: 3 h
Yield: 59.9 %

Procedure:
90 g (2.37 mole) of lithium aluminum hydride in 200 ml of diethyl ether were slowly added with stirring to a solution of 231 g (1.37 mole) of methyl quinuclidine-3-carboxylate of Example 4 in 1,000 ml of diethyl ether. Reflux was continued for 3 hours and the excess lithium alanate was carefully decomposed with 500 ml of water with proper cooling. The reaction mixture was filtered and after separation of the phases, the ether phase was dried over magnesium sulfate. Thereafter, the ether was distilled off to obtain 116 g (0.82 mole) of quinuclidine-3-methanol (60% yield) as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:15]2=[O:27])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[O:27]=[C:15]1[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(Cc3ccccc3)CC2)C(=O)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)C(=O)C1
Yield: 89.4 %

Procedure:
tert-Butyl 4-(1-benzyl-4-piperidinyl)-3-oxo-1-piperazinecarboxylate (PCT Japanese Translation Patent Publication No. 2002533451; 1.4 g) was dissolved in ethanol (30 ml), 10% palladium carbon (50% water content; 0.12 g) was added thereto, and mixed under hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a green oil (0.95 g, quantitative).
Reaction SMILES: [NH2:1][C@@:2]([C:8]1[C:13]([F:14])=[C:12]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=[C:10]([Br:22])[N:9]=1)([CH:5]([F:7])[F:6])[CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[Cl:29][CH2:30][C:31](Cl)=[O:32]>ClCCl>[Br:22][C:10]1[N:9]=[C:8]([C@@:2]([NH:1][C:31](=[O:32])[CH2:30][Cl:29])([CH2:3][OH:4])[CH:5]([F:6])[F:7])[C:13]([F:14])=[C:12]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc([C@@](N)(CO)C(F)F)c1F
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC[Si](CC)(CC)c1cc(Br)nc([C@](CO)(NC(=O)CCl)C(F)F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of (R)-2-amino-2-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-3,3-difluoro-propan-1-ol (2.15 g, 5.38 mmol) in dichloromethane (14.55 ml) was added an aq. sodium carbonate solution (14.55 ml, 10% aq. solution) at 0° C. 2-Chloroacetyl chloride (0.518 ml, 6.46 mmol) was added dropwise at 0° C. and the ice bath was removed after the addition. The reaction mixture was stirred at rt for 15 min. Methanol was added and the reaction mixture was stirred at 50° C. for 10 min. The reaction mixture was diluted with dichloromethane and water. The mixture was extracted with dichloromethane, dried over sodium sulfate, filtered and evaporated. The crude light yellow oil (2.91 g) was chromatographed over silica gel (40 g redisep column, cyclohexane/ethyl acetate 10-70%) to give the title compound. 2.32 g (91% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:10][C:11](=[O:13])[CH3:12])=[CH2:9])=[N:6][CH:7]=1>CO>[F:1][C:2]1[CH:7]=[N:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[N:4][CH:3]=1
Reactant: C=C(NC(C)=O)c1ncc(F)cn1
Solvent: CO
Product: CC(=O)N[C@@H](C)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
N-(1-(5-Fluoropyrimidin-2-yl)vinyl)acetamide (Method 58, 0.10 g, 0.55 mmol) in MeOH (5 ml) under N2 was added (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene (cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.04 g, 0.0055 mmol). The solution was transferred to a high pressure bomb and charged 150 psi H2. The reaction stirred at room temperature for 4 hours. The solvent was removed and the resulted residue was purified by column chromatography (EtOAc) to give the title compound as a white solid (0.096 g, 95%). 1H NMR (400 MHz) 8.84 (d, J=0.8 Hz, 2H), 8.34 (d, J=7.6 Hz, 1H), 5.00 (m, 1H), 1.84 (s, 3H), 1.37 (d, J=6.8 Hz, 3H). MS: Calcd.: 183. Found: [M+H]+ 184. Enantiomeric excess determined by HPLC (Chiralpak IA; 95:5 CO2/MeOH), >99% ee.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[CH3:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1>C1COCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH3:10])(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Reactant: Cc1ncc[nH]1
Solvent: C1CCOC1
Product: Cc1nccn1S(=O)(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A dry round bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with a filtered solution of 8.33 g of imidazole-4-sulfonylchloride in 300 ml of THF. The clear solution was treated with 8.45 g of 2-methylimidazole in one portion and allowed to stir overnight at room temperature. The reaction mixture was concentrated at reduced pressure to an oily residue. The residue was dissolved in 250 ml water, sodium chloride was added and the solution extracted with five 100 ml portions of ethyl acetate. The extracts were combined, washed with brine, dried (Na2SO4) and concentrated on a rotary evaporator to give 10.0 g of ivory colored product. Recrystallization from ethyl acetate-hexane have 5.57 g in two crops of 1-(4-imidazolylsulfonyl)-2-methylimidazole with mp 158°-9°, λmaxnujol 3.22 (NH), 7.30 (SO2N) and 8.48 μ (SO2N). NMR (DMSO, d6) 520-650 Hz, m, 1H; 499 Hz, d J ~ 1 Hz, 1H; 481 Hz, d, J ~ 1 Hz, 1H (AB pattern); 450 H, d, J = 1 Hz, 1H; 425 Hz, d, J = 1 Hz, 1H (AB pattern); 154 Hz, s, 3H.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:18]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:18][CH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: ClCl
Reactant: Cc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1cnc2ccccc2n1
Temperature: 68 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
2-Methylquinoxaline (8.94 g) was combined with 50 ml CCl4 and 6.5 g Na2CO3 in a 125 ml beaker. This was heated to 68° C. and then Cl2 was introduced via an inverted funnel so that the Cl2 was bubbled very slowly. This was continued for 1 hour and then the reaction mixture was cooled to 20° C. in an ice bath and partitioned between ether and saturated NaHCO3 solution. The ether was separated, dried over MgSO4, and concentrated to dryness. The residue was immediately flashed down a column packed with 20 cm of 32-63 micron silica gel (the column having a diameter of 8 cm) using 1:1 ether:hexane as eluant. After a 1 liter forerun, 250 ml fractions were collected. Fractions 3-5 were combined and concentrated to yield 2.58 g (23%) of title product as a yellow solid; tlc (3:7 ethyl acetate:CH2Cl2) Rf 0.65.
Reaction SMILES: [Br:1][C:2]1[C:3]([SH:22])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.Cl[C:24]1[CH:31]=[N:30][CH:29]=[C:28]([Cl:32])[C:25]=1[C:26]#[N:27].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[C:3]([S:22][C:24]2[CH:31]=[N:30][CH:29]=[C:28]([Cl:32])[C:25]=2[C:26]#[N:27])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: N#Cc1c(Cl)cncc1Cl
Reactant: Sc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1c(Cl)cncc1Sc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
A flask was charged with 5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridine-4-thiol (0.040 g, 0.10 mmol), 3,5-dichloroisonicotinonitrile (0.019 g, 0.11 mmol), Cs2CO3 (0.037 g, 0.11 mmol), and DMSO (2 mL). The reaction mixture was stirred at ambient temperature overnight, then quenched with water, extracted with EtOAc, dried, and concentrated. The crude material was purified by flash chromatography to provide the desired product (0.026 g, 48% yield) as a yellow solid. 1H NMR (CDCl3) δ 8.74 (d, 2H), 8.39 (s, 1H), 7.16-7.30 (m, 5H), 6.68 (s, 1H), 6.33 (s, 1H), 2.85-2.92 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2N)c1N1CC[C@@H](F)[C@@H](N)CC1

Procedure:
Following the procedure for Example 221 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid gave, after purification via silica gel column chromatography (5-7% MeOH/DCM with 1% 7 N ammonia in MeOH), 296 as a cream solid (128 mg, 59% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.13-8.08 (m, 1H), 7.84 (s, 1H), 7.40-7.32 (m, 1H), 7.29-7.20 (m, 1H), 7.17 (dd, J=11.4, 8.3 Hz, 1H), 6.10 (s, 2H), 4.89 (dd, J=47.0, 7.0 Hz, 1H), 3.74 (s, 3H), 3.50-3.31 (m, 3H), 3.22-3.09 (m, 2H), 2.37-2.27 (m, 1H), 2.12-1.89 (m, 2H), 1.86-1.78 (m, 1H). Alkyl NH2 not seen. LCMS (ES+) m/z 448 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[CH:26][N:27]=[CH:28][CH:29]=3)[CH:24]([C:31]([F:34])([F:33])[F:32])[O:23][C:21]=2[CH:22]=1>>[C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:9][O:10][C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[CH:26][N:27]=[CH:28][CH:29]=3)[CH:24]([C:31]([F:33])([F:34])[F:32])[O:23][C:21]=2[CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)C1Oc2cc(Cl)ccc2-c2ccncc21
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Product: CC(C)C[C@@H](COc1ccc2c(c1)OC(C(F)(F)F)c1cnccc1-2)NC(=O)OC(C)(C)C
Yield: 49 %

Procedure:
Prepared as described in Example 8, Part C using (S)-tert-butyl(1-hydroxy-4-methylpentan-2-yl)carbamate and 8-chloro-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridine to afford tert-butyl((2S)-4-methyl-1-((5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate (0.28 g, 0.516 mmol, 49% yield) as a yellow solid. LCMS (ESI) m/e 467.2 [(M+H)+, calcd for C24H30F3N2O4 467.2]; LC/MS retention time (Method C): tR=2.19 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][CH2:13][OH:14])[C:5]#[N:6].[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]([CH2:27][C:28](O)=[O:29])[C:19]1=[O:31])([CH3:17])=[CH2:16].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C1COCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([NH:10][CH2:11][CH2:12][CH2:13][OH:14])=[C:2]([NH:1][C:28](=[O:29])[CH2:27][N:20]2[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:18]([C:15]([CH3:17])=[CH2:16])[C:19]2=[O:31])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(NCCCO)c(N)c1
Reactant: C=C(C)n1c(=O)n(CC(=O)O)c2ccccc21
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(CC(=O)Nc2cc(C#N)ccc2NCCCO)c2ccccc21
Temperature: 23 °C
Reaction time: 48 h
Yield: 51.3 %

Procedure:
A solution of 3-amino-4-(3-hydroxy-propylamino)-benzonitrile (484 mg, 2.53 mmol) and (3-isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid (646 mg, 2.78 mmol) in THF (50 ml) was treated with EEDQ (625 mg, 2.53 mmol) and stirred for 48 h at 23° C. A grey precipitate was filtered off to give 526 mg (47%) of N-[5-Cyano-2-(3-hydroxy-propylamino)-phenyl]-2-(3-isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetamide.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:21][NH:22][C:23]([CH3:34])([CH3:33])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][OH:32])[CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[Si:36]([O:35][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][NH:22][C:23]([CH3:34])([CH3:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][OH:32])[CH:26]=1)([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:38])[CH3:37]
Reactant: [H][H]
Reactant: CC(C)(Cc1cccc(CO)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)(Cc1cccc(CO)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
A mixture of (R)-8-(benzyloxy)-5-(1-(tert-butyldimethylsilyloxy)-2-(1-(3-(hydroxymethyl)phenyl)-2-methylpropan-2-ylamino)ethyl)quinolin-2(1H)-one (Example 275, step d) (0.44 g) and palladium on carbon (10%) (80 mg) in ethanol (30 mL) was stirred vigorously under 5 bar pressure of hydrogen for 3 hours. The catalyst was filtered off and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.37 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[C:5]([O:14][CH3:15])[C:4]=1[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[C:22]([O:24][CH3:25])=[O:23].[Na].C(O)(=O)C>CO.O>[CH3:15][O:14][C:5]1[CH:6]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCCCCc1cc(OC)c(C2CCCCC2C(=O)OC)c(OC)c1
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCCCCc1cc(OC)c([C@@H]2CCCC[C@H]2C(=O)OC)c(OC)c1
Yield: 65.5 %

Procedure:
600 mg (1.7 mmol) of methyl 2-(2,6-dimethoxy-4-pentylphenyl)cyclohexane-carboxylate were dissolved in 10 ml of methanol, a solution of 200 mg (8.7 mmol) of sodium in 7.5 ml of methanol was added, and the mixture was heated under reflux overnight. The mixture was subsequently diluted with water, acidified using acetic acid and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and evaporated, giving 388 mg (75%) of methyl trans-2-(2,6-dimethoxy-4-pentyl-phenyl)cyclohexanecarboxylate as a colourless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([O:24][CH2:25][CH:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C1COCC1.ClCCl>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([O:24][CH2:25][CH:26]4[CH2:30][CH2:29][CH2:28][N:27]4[CH2:2][CH2:3][CH2:4][C:5]#[N:6])=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4CCCN4)c23)cc1
Reactant: N#CCCCBr
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4CCCN4CCCC#N)c23)cc1
Temperature: 25 °C

Procedure:
Add 221.2 mg (0.996 mmol) of 4-bromobutyronitrile at RT to a solution of 300 mg (0.747 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-4-(pyrrolidin-2-ylmethoxy)furo[2,3-d]pyrimidine, 0.37 ml (2.24 mmol) of diisopropylethylamine and 12.4 mg of potassium iodide in 3 ml of THF. Stir the mixture under reflux for 6 h. After cooling to RT, dilute with dichloromethane, wash with satd. sodium hydrogencarbonate solution, remove the organic phase, dry over sodium sulphate and concentrate under reduced pressure. After drying the residue by means of preparative RP-HPLC (eluent: acetonitrile/water gradient), 178.1 mg of the target product are obtained (50.9% of theory).