Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:23](=[O:24])[N:12]2[C@@H:13]([C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[C:14](=O)[CH2:15][C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[CH2:51]([O:54][C:55]([N:57]1[CH2:61][C@@H:60]([SH:62])[CH2:59][C@H:58]1[CH2:63][OH:64])=[O:56])[CH:52]=[CH2:53]>C(#N)C>[CH2:51]([O:54][C:55]([N:57]1[CH2:61][C@@H:60]([S:62][C:14]2[CH2:15][C@@H:11]3[C@@H:10]([C@H:8]([O:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH3:9])[C:23](=[O:24])[N:12]3[C:13]=2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:59][C@H:58]1[CH2:63][OH:64])=[O:56])[CH:52]=[CH2:53]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CO
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2[C@@H](C(=O)OCC=C)C(=O)C[C@H]12
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(S[C@H]3C[C@@H](CO)N(C(=O)OCC=C)C3)C[C@H]12
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of allyl (3R,5R,6S)-6-[(R)-1-allyloxycarbonyloxyethyl]-2-oxo-1-carbapenam-3-carboxylate (1.01 g, 3 mmol) and N,N-diisopropylethylamine (0.73 ml, 4.2 mmol) in acetonitrile (20 ml) was dropwise added diphenyl chlorophosphate (0.75-3.6 mmol) under ice-cooling, and then the mixture stirred for 30 minutes. The reaction mixture under ice-cooling was treated successively with N,N-diisopropylethylamine (0.73 μl, 4.2 mmol) and (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-mercaptopyrrolidine (780 mg, 3.6 mmol) in acetonitrile (4 ml), stirred for 1 hour, and partitioned between ethyl acetate (60 ml) and water (40 ml). The organic layer was successively washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the residue purified by flash column chromatography on silica gel (Wakogel® C-300, 40 ml, elution with ethyl acetate-hexane 1:1) to afford the title compound (1.20 g, 75% yield).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:22]([O:24][C:25](=[O:32])[CH:26]([CH2:30][CH3:31])[C:27](O)=[O:28])[CH3:23]>>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[C:27](=[O:28])[CH:26]([C:25]([O:24][CH2:22][CH3:23])=[O:32])[CH2:30][CH3:31])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(=O)C(CC)C(=O)O
Agent: [Cl-]
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)C(CC)C(=O)OCC

Procedure:
The starting material can be prepared, for example, as follows: Analogously to Example 4b) and using 2.64 g of N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 2.68 g of ethylmalonic acid monoethyl ester monochloride as starting materials, there is obtained 2-ethoxycarbonylbutanoic acid N-butyl-N-(2'-cyano-biphenyl-4-ylmethyl)-amide that has an Rf value of 0.65 [CH2Cl2 /CH3OH (95:5)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:18]=[C:11]2[N:12]=[C:13]([CH3:17])[NH:14][C:15](=[O:16])[N:10]2[N:9]=1.[I:19]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]([I:19])=[C:11]2[N:12]=[C:13]([CH3:17])[NH:14][C:15](=[O:16])[N:10]2[N:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1nc2cc(-c3ccccc3Cl)nn2c(=O)[nH]1
Solvent: ClCCl
Product: Cc1nc2c(I)c(-c3ccccc3Cl)nn2c(=O)[nH]1
Reaction time: 5 h
Yield: 90.9 %

Procedure:
To a suspension of 7-(2-chlorophenyl)-2-methyl-3H-pyrazolo[1,5-a]-[1,3,5]triazin-4-one (I-1A-1c; 18.9 g, 72.6 mmol) in methylene chloride (290 ml) cooled in an ice bath was added N-iodosuccinimide (18.0 g, 79.9 mmol). The mixture became homogeneous orange solution within 5 minutes. After stirring for 5 hours, the mixture was washed with 50% saturated aqueous NH4OH (160 ml), 1 M aqueous Na2S2O3 (120 ml), and brine (120 ml). The solution was concentrated, in vacuo, and then concentrated again from MTBE (150 ml). Additional MTBE (75 ml) was added and stirred for 1 hour. The resulting solid precipitate was collected by vacuum filtration in a course sintered glass funnel, washed with MTBE (50 ml) and then dried, in vacuo, to afford product I-1A-1d as a solid (25.5 g, 91%): +APcI MS (M+1) 387.3; 1H NMR (400 MHz, CD3OD) δ 7.54 (d, J=7.1 Hz, 1H), 7.51-7.39 (m, 3H), 2.45 (S, 3H).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[Br:5][C:6]1[S:16][C:9]2[N:10]=[C:11]([CH3:15])[N:12]=[C:13](Cl)[C:8]=2[CH:7]=1.O>C1COCC1>[Br:5][C:6]1[S:16][C:9]2[N:10]=[C:11]([CH3:15])[N:12]=[C:13]([O:2][CH3:1])[C:8]=2[CH:7]=1
Reactant: CO
Reactant: Cc1nc(Cl)c2cc(Br)sc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C)nc2sc(Br)cc12
Reaction time: 0.25 h

Procedure:
A mixed solution of MeOH (2 mL) and THF (15 mL) was cooled in an ice bath, and NaH (60% oil, 600 mg) was added thereto, followed by stirring for 15 minutes. Then, a solution of 6-bromo-4-chloro-2-methylthieno[2,3-d]pyrimidine (2.0 g) in THF (5 mL) was added thereto, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain 6-bromo-4-methoxy-2-methylthieno[2,3-d]pyrimidine (1.8 g).
Reaction SMILES: [Na].[C:2]1([CH3:9])[C:3](C)=[CH:4][CH:5]=[CH:6][CH:7]=1.[P:10]([O-:17])([O:14]CC)[O:11]CC.C(Cl)(Cl)C1C=CC=CC=1>O1CCCC1>[C:2]1([CH:9]([P:10]([OH:17])(=[O:11])[OH:14])[P:10]([OH:17])(=[O:14])[OH:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C
Reactant: CCOP([O-])OCC
Agent: [Na]
Solvent: C1CCOC1
Solvent: ClC(Cl)c1ccccc1
Product: O=P(O)(O)C(c1ccccc1)P(=O)(O)O
Temperature: 62 °C

Procedure:
There were charged into the reaction vessel 23.0 grams (1.0 mole) of sodium metal along with 90 cc. of xylene and 80 cc. of tetrahydrofurane. The vessel was placed under a nitrogen blanket and 138.10 grams (1.0 mole) of diethyl phosphite added over a 35 minute period. An exothermic reaction ensued which was maintained at 62° C. by external cooling. After addition was complete the mixture was heated to 100° C. and held there until all of the sodium metal was gone. The mixture was cooled to 60° to 70° C. and 80.50 grams (0.5 ,ole) of benzal chloride were added gradually over a 25 minute period. An exothermic reaction ensued which was maintained at 60° to 70° C. by external cooling. The mixture was then heated for 4 hours at 70° to 75° C., cooled to 60° C. The liquid material was separated from the solid and the solid boiled 8 times with 100 cc. of benzene to extract the organic material. The eluate product was then distilled, terminal conditions being a pot temperature of 201° C., distillate temperature 125° C. and pressure 6 mm. The solid residue of 70 grams was tetraethyl phenyl methane diphosphonate. This product was hydrolyzed and the hydrolysis product purifid as in Example 1 to obtain phenyl methane diphosphonic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH3:20])[C:17](Cl)=[O:18].[CH3:28][NH2:29].O.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH3:20])[C:17]([NH:29][CH3:28])=[O:18]
Reactant: CN
Reactant: CC(C(=O)Cl)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CNC(=O)C(C)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
A solution of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetyl chloride (0.007 mol) in CH2Cl2 (20 ml) was added at RT to methanamine 40% in water (0.105 mol). The mixture was stirred at RT for 4 hours, then poured out into water, acidified with HCl (3N) and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 1.25 g (43%) of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α,N-dimethylbenzeneacetamide (comp. 1.14).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[Br:8][C:9]1[C:17]2[N:16]([CH3:18])[C:15]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[N:26]=[CH:27][NH:28][C:29]=4[CH3:30])[C:22](=[O:23])[C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[Br:8][C:9]1[C:17]2[N:16]([CH3:18])[C:15]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[N:26]=[CH:27][N:28]([S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[C:29]=4[CH3:30])[C:22](=[O:23])[C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1[nH]cnc1CN1CCc2c(c3cccc(Br)c3n2C)C1=O
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CN2CCc3c(c4cccc(Br)c4n3C)C2=O)ncn1S(=O)(=O)N(C)C
Reaction time: 60 h

Procedure:
Dimethylsulphamoyl chloride (0.31 ml) was added dropwise to a stirred suspension of 6-bromo-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl) methyl]-1H-pyrido[4,3-b]indol-1-one (1.1 g) and triethylamine (0.48 ml) in dry dichloromethane (100 ml). The mixture was heated at reflux for 18 h, then a further quantity of triethylamine (0.48 ml) and dimethylsulphamoyl chloride (0.31 ml) was added. The solution was heated at reflux for 8 h then left at 21° for ca. 60 h. The solution was concentrated in vacuo and purified by FCC eluting with System A (100:8:1) to give a solid, which was triturated with hexane (50 ml) to give the title compound (500 mg), m.p. 182°-185°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](C(C)OCC)[CH:11]=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.CN(C)[CH:41]=[O:42]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([CH:41]=[O:42])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: CCOC(C)n1cnc(-c2ccc(SC)cc2)c1-c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(-c2nc(C=O)[nH]c2-c2ccc(F)cc2)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A solution of the compound from step 2 (500 mg, 1.4 mmol) and tetramethylethylenediamine (TMEDA) (186 mg, 1.6 mmol) in tetrahydrofuran (8 ml) was cooled to −70° C. under an argon atmosphere. n-Butyllithium (1.2 ml of 1.6M solution in hexane, 1.9 mmol) was added and the solution stirred at −70° C. for 15 minutes. Dimethylformamide (DMF) (140 mg, 1.9 mmol) was added and the solution was warmed to 0° C. The reaction was quenched by the addition of saturated NaHCO3 solution (2 ml) and extracted with diethyl ether. The organic phase was separated and dried (Na2SO4). The drying agent was filtered and the filtrate concentrated in vacuo. The residue was treated with 2N HCl (5 ml) in EtOH (10 ml) at room temperature for 24 hours. The reaction solution was made basic with NaHCO3, diluted with water (20 ml) and extracted with methylene chloride. After evaporation, the residue was purified by chromatography on silica gel, eluting with toluene/methanol (90/10), to give 350 mg (70%) of titled compound which was used immediately without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH3:12])[O:5][N:4]=1)[CH3:2].C([Li])CCC.CCCCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH2:12][CH:24]([OH:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(C)c1C(=O)NC
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1noc(CC(O)c2ccccc2)c1C(=O)NC
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 58.5 g. (0.348 mole) of 3-ethyl-N,5-dimethyl-isoxazole-4-carboxamide and 1 liter of tetrahydrofuran is cooled to -65° C. and 478 ml. of 1.6 M n-butyllithium in hexane (0.765 mole) is added dropwise maintaining the temperature between -60° and -70° C. After the addition is complete, the suspension is stirred for 11/2 hours at -60° to -70° C., and then 37.2 g. (0.350 mole) of benzaldehyde in 375 ml. tetrahydrofuran is added dropwise maintaining the temperature between -60° and -70° C. After addition is complete, the mixture is stirred for 11/2 hours at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with ether and filtered to give 3-ethyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide, m.p. 135° to 137° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:14]([Cl:16])=[O:15])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8](Cl)=[O:9])#[N:2].[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>O1CCOCC1>[C:1]([C:3]1[C:11]([I:12])=[C:7]([C:8](=[O:9])[NH:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22])[C:6]([I:13])=[C:5]([C:4]=1[I:17])[C:14]([Cl:16])=[O:15])#[N:2]
Reactant: N#Cc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: NCC(O)CO
Solvent: C1COCCO1
Product: N#Cc1c(I)c(C(=O)Cl)c(I)c(C(=O)NCC(O)CO)c1I
Reaction time: 2 h

Procedure:
18.1 g of 5-cyano-2,4,6-triiodoisophthalic acid dichloride is combined in 750 ml of dioxane at 80° C. with 7.1 g of 1-amino-2,3-propanediol and stirred for 2 hours. The mixture is then separated from the precipitated hydrochloride of 1-amino-2,3-propanediol, and the filtrate is concentrated under vacuum. The residue is extracted by boiling with 800 ml of ethyl acetate. After concentration and cooling, 11.7 g (59% of theory) of 5-cyano-3-[N-(2,3-dihydroxypropyl)carbamoyl]-2,4,6-triiodobenzoyl chloride is crystallized from the extract as a white powder; mp 285°-288° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].NC1C=C(C)C(O)=C(C)C=1.C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[Cl:49][C:50]1[N:55]=[C:54](Cl)[C:53]([F:57])=[CH:52][N:51]=1>>[Cl:49][C:50]1[N:55]=[C:54]([NH:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([OH:12])=[C:4]([CH3:11])[CH:5]=2)[C:53]([F:57])=[CH:52][N:51]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: Cc1cc(N)cc(C)c1O
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Cc1cc(Nc2nc(Cl)ncc2F)cc(C)c1O

Procedure:
Using general hydrogenation conditions, 2,6-dimethyl-4-nitrophenol was reduced to 4-amino-2,6-dimethylphenol. In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 4-amino-2,6-dimethylphenol (823 mg, 6 mmol) and 2,4-dichloro-5-fluoropyrimidine (500 mg, 3 mmol) gave 2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine. Compound 2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine (500 mg, 1.87 mmol) and 3-(methoxycarbonylmethyleneoxy)aniline (500 mg, 2.76 mmol) reacted to give N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (500 mg, 65%). 1H NMR (CD3OD): δ 2.16 (s, 6H), 3.76 (s, 3H), 4.51 (s, 2H), 6.79 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 7.01–7.06 (m, 2H), 7.15 (s, 2H), 7.26 (t, J=8.1 Hz, 1H), 7.93 (d, J=5.7 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −163.31; LCMS: ret. time: 20.44 min.; purity: 84.25%; MS (m/e): 413.03 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:16]=[C:17]([Cl:21])[CH:18]=[CH:19][CH:20]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cc(Br)ccc2OC2CCNCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Yield: 97.5 %

Procedure:
In a manner similar to the method described in Example 38a, racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-6-chloro-2′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.75 g, 1 mmol) was reacted with trifluoroacetic acid in dichloromethane to give title compound as a yellow solid (Yield: 0.6 g, 93%).
Reaction SMILES: [C:1]([O-])([O-])=[O:2].[K+].[K+].FC1C=CC=CC=1CBr.[CH3:16][O:17][C:18]1[C:23](C)=[CH:22][C:21]([N:25]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[C:38]([F:39])=[CH:37][C:36](F)=[CH:35][C:34]=3F)[C:28]3[CH:42]=[CH:43][CH:44]=[CH:45][C:27]=3[S:26]2(=[O:47])=[O:46])=[CH:20][C:19]=1C>CN(C=O)C>[CH3:1][O:2][C:19]1[CH:20]=[C:21]([N:25]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[F:39])[C:28]3[CH:42]=[CH:43][CH:44]=[CH:45][C:27]=3[S:26]2(=[O:46])=[O:47])[CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: O=C([O-])[O-]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: Fc1ccccc1CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)N(Cc3ccccc3F)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (64 mg, 0.14 mmol) was prepared from (IntA1) (67 mg, 0.20 mmol), K2CO3 (83 mg, 0.60 mmol) and 2-fluorobenzyl bromide (45 mg, 0.24 mmol) in DMF (2 mL) using the methods of (115).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:20]([O-:23])(=[O:22])[CH3:21].[NH2:24][N+:25]1[CH:29]=[CH:28][N:27]([NH2:30])[C:26]=1[CH2:31][CH3:32]>C(O)(=O)C.C(O)C>[C:20]([O-:23])(=[O:22])[CH3:21].[C:20]([O-:23])(=[O:22])[CH3:21].[C:20]([O-:23])(=[O:22])[CH3:21].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[N:24][N+:25]3[CH:29]=[CH:28][NH:27][C:26]=3[CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:16]=[N:30][N+:27]3[CH:28]=[CH:29][NH:25][C:26]=3[CH2:31][CH3:32])=[CH:18][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[N:24][N+:25]3[CH:29]=[CH:28][NH:27][C:26]=3[CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCc1n(N)cc[n+]1N
Reactant: CCOC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)N1CCN(c2ccc(C=N[n+]3cc[nH]c3CC)cc2)CC1
Reaction time: 18 h

Procedure:
1.95 g (7.4 mmol) of p-[4-(ethoxycarbonyl)-1-piperazinyl]benzaldehyde are added to a solution of 0.69 g (3.7 mmol) of 1,3-diamino-2-ethyl-imidazolium acetate in 10 ml of glacial acetic acid, the mixture is left to stand at room temperature for 18 hours, then diluted with 30 ml of ethanol and the product is crystallized out by the addition of ether. There is obtained 1,3-bis[[[p-(4-(ethoxycarbonyl)-1-piperazinyl]benzylidene]amino]-2-ethyl-imidazolium acetate diacetate of melting point 187°-188°.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[C:20](Cl)([Cl:22])=[O:21]>ClCCl>[F:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][N:7]([C:20]([Cl:22])=[O:21])[CH2:6][CH2:5]1
Reactant: OC1(CF)CCNCC1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)N1CCC(O)(CF)CC1
Reaction time: 0.25 h
Yield: 37 %

Procedure:
4-(Fluoromethyl)piperidin-4-ol hydrochloride (233 mg, 1.37 mmol) was suspended in dichloromethane (3 mL) followed by addition of DIPEA (0.6 mL, 3.4 mmol) and the slurry obtained added in portions over several minutes to a solution of phosgene (20W % in toluene, 0.75 mL) diluted into dichloromethane (5 mL) and the mixture was allowed to stir at this temperature for 15 minutes. The mixture was then concentrated and the residue partitioned with ethyl acetate and water. The organic solution was washed 0.5M hydrochloric acid, brine then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3:1 ethyl ether:hexanes) to give 4-(fluoromethyl)-4-hydroxypiperidine-1-carbonyl chloride (100 mg, 37% yield) as a colorless amorphous residue. GC-MS (EI) for C7H11FNO2Cl: 196 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH2:11][C:12]([OH:14])=O.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29]([NH2:56])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]=[CH:45][N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=3)[S:42][C:35]=12.C(Cl)CCl>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([NH:56][C:12](=[O:14])[CH2:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:15])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]=[CH:45][N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:54])([CH3:53])[CH3:55])[CH:47]=3)[S:42][C:35]=12
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(COCC[Si](C)(C)C)cn4)sc23)c(F)c1
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
To a solution of the acid 27 (59 mg, 2 eq, 0.28 mmol) and HOBT (19 mg, 1 eq, 0.14 mmol) in DMF (3 ml) was added amine 104 (64 mg, 0.14 mmol) and the reaction mixture was stirred for 10 mins. EDC (54 mg, 2 eq, 0.28 mmol) was added and the reaction mixture was stirred at RT overnight. The solvents were removed and the residue was partitioned between EtOAc and water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (20% acetone in hexane to 100% acetone) afforded title compound 105 (53 mg, 58% yield). MS (m/z): 648.2 (M+H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f24) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([NH:12]C(=O)C2C=C(C)C=NC=2)[CH:9]=[CH:10][CH:11]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](Cl)=[O:30])=[N:27][CH:28]=1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:29]([C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=2)=[O:30])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)c1ccc(F)cn1
Reactant: Cc1cncc(C(=O)Nc2cccc(C3OCCO3)c2)c1
Product: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(F)cn1

Procedure:
The subtitle compound is prepared according to the reaction 4.01a described above using 5-fluoropicolinoyl chloride: LC-MS A: tR=0.89 min; [M+H]+=289.29.