Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[O:25]1[CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23][CH2:24]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(-c2cncnc2)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
5-Bromo-6-morpholino-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 148.1, 60 mg, 0.134 mmol), pyrimidin-5-ylboronic acid (50 mg, 0.403 mmol), Pd(Ph3P)4 (12.43 mg, 10.76 μmol) and finely ground K3PO4 (143 mg, 0.672 mmol) were added to a MW vial and treated with toluene (672 μL). The vial was sealed, evacuated/purged with argon then the RM was stirred 110° C. for 16 h, diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 56.0 mg, 0.081 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column Diol, from 15% to 20% in 6 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=1.00 min, m/z=446.3 [M+H]+, m/z=444.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.09-3.20 (m, 4H) 3.50-3.60 (m, 4H) 7.38 (d, J=8.28 Hz, 2H) 7.86 (d, J=9.16 Hz, 2H) 8.23 (d, J=2.38 Hz, 1H) 8.84 (d, J=2.38 Hz, 1H) 9.13 (s, 2H) 9.22 (s, 1H) 10.37 (s, 1H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.CC(O)=O>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])/[CH:11]=[CH:17]/[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[O:14][CH3:13])=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: COc1ccccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1/C=C/C(=O)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 96.8 %

Procedure:
KOH (1.415 g, 25.2 mmol) was added to a solution of 1-(4-chlorophenyl)ethanone (3.9 g, 25.2 mmol) and 2-methoxybenzaldehyde (3.43 g, 25.2 mmol) in methanol (100 ml) at RT and the solution was stirred for 18 hours. The solution was concentrated under reduced pressure until a precipitate was formed. AcOH (1.444 ml, 25.2 mmol) was added and the mixture was cooled down to 0° C.-5° C. The mixture was stirred for 1 hour and the light yellow precipitate was separated by filtration and washed with cold methanol to afford 6.72 g (24.39 mmol, 97% yield) of the title compound. LCMS: (M+H)=273; tR=1.28 min (LC-MS 3). 1H-NMR (d6-DMSO, 600 MHz) δ ppm 8.12 (d, 2H) 8.04 (d, 1H) 7.98 (d, 1H) 7.86 (d, 1H) 7.62 (d, 2H) 7.45 (t, 1H) 7.10 (d, 1H) 7.02 (t, 1H) 3.88 (s, 3H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([NH2:18])=[O:17])[C@@H:13]([CH3:15])O)=O)C1C=CC=CC=1.C[S:20](Cl)(=[O:22])=[O:21].[OH2:24]>N1C=CC=CC=1>[NH2:11][C@H:12]1[C@H:13]([CH3:15])[N:18]([S:20]([OH:22])(=[O:24])=[O:21])[C:16]1=[O:17]
Reactant: C[C@@H](O)[C@H](NC(=O)OCc1ccccc1)C(N)=O
Reactant: CS(=O)(=O)Cl
Reactant: O
Solvent: c1ccncc1
Product: C[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of argon, 100 g of benzyloxycarbonylthreonine amide is dissolved in 400 ml of anhydrous pyridine and cooled in an ice/salt bath. To this stirring solution, 36.8 ml (54.5 g) of methanesulfonyl chloride is added over a 15 minute period. After 2 hours of stirring an additional 0.3 equivalents of methanesulfonyl chloride is added. The reaction is then stirred for 1 hour and poured into a mixture of 1.5 l of ice and 2 l of water. The resulting slurry is stirred for about 30 minutes and filtered. Drying of the crude product at 60° C. for about 16 hours in a vacuum oven gives 109 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](C3C=CC(Br)=CC=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29](C2C=CC(C)=CC=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:55][O:56][C:57]([C:59]1[CH:60]=[C:61](B(O)O)[CH:62]=[CH:63][CH:64]=1)=[O:58]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:43]=[C:44]([C:47]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:45]([C:63]3[CH:62]=[CH:61][CH:60]=[C:59]([C:57]([O:56][CH3:55])=[O:58])[CH:64]=3)=[CH:46][CH:47]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:11][C:10]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:9]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(Br)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Product: COC(=O)c1cccc(-c2ccc(CN(C(=O)CN(C)S(=O)(=O)c3ccc(C)cc3)c3ccc(C(=O)OCc4ccccc4)c(OCc4ccccc4)c3)cc2-c2ccccc2)c1
Yield: 38 %

Procedure:
Aryl halide 5 was coupled to 3-(methoxycarbonyl)phenylboronic acid on a 0.1 mmol scale via General Procedure H to yield 35 (39 mg, 38%): δH (400 MHz, CDCl3) 2.40 (s, 3H, CH3), 2.83 (s, 3H, CH3), 3.68 (s, 2H, CH2), 3.96 (s, 3H, CH3), 4.84 (s, 2H, CH2), 5.02 (s, 2H, CH2), 5.35 (s, 2H, CH2), 6.62 (s, 1H, CH), 6.70 (d, J=8.0 Hz, 1H, CH) 7.19 (d, J=8.0 Hz, 2H, CH), 7.26-7.34 (m, 10H, CH), 7.38-7.41 (m, 3H, CH), 7.54 (d, J=8.0 Hz, 2H, CH), 7.62 (d, J=8.4 Hz, 2H, CH), 7.68 (q, J=8.0 Hz, 4H, CH), 7.84 (t, J=8.0 Hz, 2H, CH), 8.03 (d, J=8.0 Hz, 1H, CH), 8.32 (s, 1H, CH); LRMS (ES+) Calcd for [C52H46N2O8S+H] 859.31. found 859.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[Br:12]N1C(=O)CCC1=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][Br:12])[C:6]=2[CH:11]=1
Reactant: Cc1csc2ccc(Cl)cc12
Reactant: O=C1CCC(=O)N1Br
Product: Clc1ccc2scc(CBr)c2c1

Procedure:
Reaction of chloroacetone with 4-chlorothiophenol gave (4-chlorophenyl)thiomethyl methyl ketone, which was cyclized by reaction with polyphosphoric acid to 5-chloro-3-methylbenzothiophene. Bromination of the latter compound by photochemical reaction with N-bromosuccinimide provided 5-chloro-3-bromomethylbenzothiophene, which was reacted with sodium cyanide to give 5-chloro-3-cyanomethylbenzothiophene. The latter compound was hydrolyzed and esterified to give methyl α-(5-chloro-3-benzothienyl)acetate. Reaction of the ester with sodium methoxide and n-butyl nitrite afforded methyl α-hydroxyimino-α-(5-chloro-3-benzothienyl)acetate. Reduction of the oxime by reaction with zinc and formic acid and subsequent reaction with di-tert.-butyl carbonate gave N-tert.-butoxycarbonyl-(5-chloro-3-benzothienyl)glycine. NMR (CDCl3): δ 1.1-1.5 (broad s, 9H); δ 5.4-5.7 (broad s, 1H); δ 7.2-8.0 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:32])[CH:28]([CH3:31])[CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:32])[CH:28]([CH3:31])/[CH:29]=[CH:30]/[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C=CC(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(C)/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 168, Step 1, using 1-{4′-[4-(1-hydroxy-2-methyl-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[O:23]=[C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][C:32]([OH:34])=[O:33].N12CCCN=C1CCCCC2.O>CN(C)C=O>[O:23]=[C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][C:32]([O:34][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:33]
Reactant: O=C(O)CCN1CCCCC1=O
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCN1CCCCC1=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 46.9 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (4,3 g) in anhydrous dimethylformamide (40 cc), 3-(2-oxopiperidino)propionic acid (2.2 g) and 1,8-diazabicyclo [5.4.0]undec-7-ene (2 g). After the reaction mixture has been taken up with water, the resulting mixture extracted with methylene chloride and the solvent evaporated, the residue obtained is recrystallized in acetonitrile. The product thereby obtained is purified by chromatography on silica (0.063-0.2 mm; 100 g) contained in a column 2.3 cm in diameter (eluant: methylene chloride), collecting 50-cc fractions. Fractions 56 to 64 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 20° C. The residue obtained is recrystallized in acetonitrile. 2-(7-Chloro-1,8-naphthridin-2-yl)-3-oxo-1-isoindolinyl 3-(2-oxopiperidino)propionate (2.8 g), m.p. 175° C., is thereby obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2S[CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.ClC1C=CC=C(C(OO)=O)C=1.[S:28]([O-:32])([O-])(=[O:30])=S.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:28](=[O:32])(=[O:30])[CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: O=S([O-])([O-])=S
Reactant: COC(=O)C1=Cc2cc(Br)ccc2SCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1

Procedure:
To a solution of methyl 7-bromo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.8 g) in THF (10 ml) was added at 0° C. 70% 3-chloroperbenzoic acid (1.45 g), and the mixture was stirred at 0° C. for 30 minutes and further at room temperature for 1 hour. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with column chromatography (ethyl acetate/hexane=1:1) and recrystallized from ethyl acetate/hexane to give pale yellow crystals of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (827 mg). 1H-NMR (200 MHz, CDCl3) δ 3.11 (2H, t, J=6.5 Hz), 3.62 (2H, t, J=6.5 Hz), 3.87 (3H, s), 7.64-7.76 (3H, m), 8.03 (1H, d, J=8.4 Hz). IR (KBr) 1718, 1288, 1263, 1165, 1128, 1090, 797, 748 cm−1; Anal. for C12H11O4SBr; Calcd. C, 43.52; H, 3.35; Found. C, 43.39; H, 3.38.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].[NH4+].[Cl-].CO>[Fe].O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnn(-c2ccc([N+](=O)[O-])cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cnn(-c2ccc(N)cc2)c1
Temperature: 100 °C
Yield: 57.6 %

Procedure:
A mixture of 1-(4-nitrophenyl)-1H-pyrazol-4-carboxylic acid methyl ester (19.44 g), Fe powder, NH4Cl, methanol and H2O was heated for 30 minutes at 80° C. for 3 hours at 100° C. The reaction mixture was concentrated by evaporation, added into dichloromethane, and was filtered. The filtrate was extracted with water, dried over magnesium sulfate and concentrated by evaporation to give 1-(4-aminophenyl)-1H-pyrazol-4-carboxylic acid methyl ester (9.84 g).
Reaction SMILES: Cl.C([O:4][C:5](=[O:19])[CH:6]([NH:15][CH:16]([CH3:18])[CH3:17])/[CH:7]=[C:8](\[CH3:14])/[CH2:9][P:10]([OH:13])([OH:12])=[O:11])C>O>[CH:16]([NH:15][CH:6](/[CH:7]=[C:8](\[CH3:14])/[CH2:9][P:10]([OH:13])([OH:12])=[O:11])[C:5]([OH:19])=[O:4])([CH3:18])[CH3:17]
Reactant: CCOC(=O)C(/C=C(\C)CP(=O)(O)O)NC(C)C
Agent: Cl
Solvent: O
Product: C/C(=C\C(NC(C)C)C(=O)O)CP(=O)(O)O

Procedure:
A solution of 1.20 g of E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoicacid ethyl ester hydrochloride in 7 ml of water is stirred under reflux for20 hours. The reaction mixture is concentrated to dryness by evaporation invacuo. Ethanol is added to the residue, and the mixture is again concentrated by evaporation. This process is repeated twice more. The residue is dissolved in 25 ml of ethanol, a total of 5 ml of propylene oxide is added dropwise thereto with stirring, and the whole is concentrated to dryness by evaporation. The residue is dissolved in a little water, and ethanol is added until the solution becomes cloudy. The solution is stirred at room temperature for 4 hours to complete the reaction, during which time crystallisation slowly takes place. The product is filtered off, washed with ethanol and diethyl ether and dried at 100° under a high vacuum. In this manner there is obtained E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 225°-227° (decomp.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][C:12]([CH3:19])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:22])=[N:13][C:12]([CH3:19])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(c(=O)[nH]1)CCN(Cc1ccccc1)C2
Product: Cc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 25 °C

Procedure:
7-Benzyl-2-methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (prepared according to the method of Example 86, Step A, 17.1 g, 67.0 mmol) was suspended in phosphorus oxychloride (66 mL, 335 mmol). This mixture was stirred at reflux for 1 h, cooled to room temperature, evaporated, then chased with toluene. The residue was carefully diluted with ice/water/chloroform and the layers were separated. The aqueous phase was extracted with chloroform (3×) and the combined organic extracts were washed with saturated aqueous sodium bicarbonate (1×) and water (1×), dried over sodium sulfate, filtered, and evaporated to give the title compound of Example 86, Step B as a brown oil that was used without purification in the next step. 1H NMR (CDCl3, 250 MHz) δ 7.36-7.23 (c, 5H), 3.73 (s, 2H), 3.63 (s, 2H), 2.63 (app s, 4H), 2.36 (s, 3H); MS (APCI) 274, 276 (MH+).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1.CCCCCC>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
804 mg (3.2 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) is dissolved in 16 ml dry THF and cooled to −78° C. After the addition of 2.21 ml butyl lithium in hexane (1.59 M), the yellow solution is stirred at −78° C. for 30 min. Subsequently, 680 l (640 mg=3.84 mmol) (2-chloromethoxyethyl)-trimethylsilane (SEM-Cl) is added and stirring is continued at −20° C. for 5 h. The mixture is then allowed to warm up to room temperature overnight. The reaction is then quenched by addition of 10 ml saturated NH4Cl solution followed by 10 ml water and extracted with 2×40 ml isopropyl acetate. The layers are separated and the organic layer dried over MgSO4, filtered and evaporated. The resulting residue (1.33 g) is purified using column chromatography (dichloromethane:triethylamine=99.5:0.5→dichloromethane:methanol:triethylamine=98.5:1:0.5) to give (S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one (1-a, R1=SEM) as a yellow oil. NMR (400 MHz, CDCl3, /ppm): 7.58 (m, 4H); 7.47 (m, 2H); 7.37 (m, 1H); 7.30 (m, 2H); 5.04 (d, J=10.6, 1H); 4.70 (d, J=10.6, 1 H); 4.03 (m, 1H); 3.59 (m, 2H); 3.24 (dd, J=4.2, 13.4, 1H); 2.67 (dd, J=9.1, 13.4, 1H); 2.33 (t, J=8.2, 2 H); 2.10 (m, 1H); 1.81 (m, 1H); 1.00 (m, 2H); 0.06 (s, 9H). MS (ESI, m/e) 382 [M+H]+; 763 [2M+H]+. IR (solution in CH2Cl2, /cm−1): 3057; 2951; 1702; 1487; 1414; 1249; 1073; 859; 836; 759; 697.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:30])[C:26]([OH:29])([CH3:28])[CH3:27])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[CH3:31]I>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:30])[C:26]([O:29][CH3:31])([CH3:28])[CH3:27])[CH2:22][CH2:23]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1
Reactant: CI
Reactant: CC(C)(O)C(=O)NC1CCC(CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Product: COC(C)(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (3 mg, 13.1%), MS (ISP) m/z=432.4 [(M+H)+], was prepared in accordance with the general method of example 62 from N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-2-methyl-propionamide (20 mg, 47.9 mmol) and methyl iodide.
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)[CH:8]=1)([CH3:6])[C:3](O)=[O:4].[CH3:38][NH:39][CH3:40].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[OH:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:16]3=[N:17][CH:18]=2)[CH:8]=1)([CH3:6])[C:3]([N:39]([CH3:40])[CH3:38])=[O:4]
Reactant: CNC
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C)(O)C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C)(O)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of 2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-propionic acid (100 mg, 0.19 mmol), dimethylamine (2 N in THF, 0.143 mL, 0.29 mmol), and diisopropylethylamine (37 mg, 0.29 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 547 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30]>C(#N)C>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH:30][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(CNCCOc2cccc(-c3noc4ccsc34)c2)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3-fluorobenzylamine and acetonitrile essentially as described above in example 18 except that the column is eluted using a graded solvent mixture of 40% ethyl acetate in heptane to 100% ethyl acetate. Purity by LC/MS (APCI)=100%, [M+H]+=369.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16]>C(OCC)(=O)C>[ClH:11].[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH2:12][CH2:13][CH2:14][C:15]2=[NH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCCCCl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: Cl
Product: N=C1CCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 190 °C

Procedure:
A mixture of 40.0 g (290 mmol) of 4-nitroaniline and 40.0 ml (421 mmol) of 4-chlorobutyronitrile is heated at the boil (about 190° C.) for 30 minutes using a hot-air fan. The mixture is allowed to cool and is digested with ethyl acetate, giving 1-(4-nitrophenyl)pyrrolidin-2-ylideneamine, hydrochloride, as a brown solid, ESI 206.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:14]2[CH:18]=[C:17]([C:19]([O:21]CC)=[O:20])[CH:16]=[N:15]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:14]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[N:15]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)C)c(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)COc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 80 °C
Yield: 55.7 %

Procedure:
To a solution (15 ml) of ethyl 1-(3-cyano-4-isobutoxyphenyl)pyrazole-4-carboxylate (1.38 g) in ethanol was added 1.75 N aqueous sodium hydroxide solution (3 ml) with stirring, and the mixture was heated at 80° C. for 30 minutes. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solvent of dioxane and water to give 0.7 g of 1-(3-cyano-4-isobutoxyphenyl)pyrazole-4-carboxylic acid, melting point 192-194° C.
Reaction SMILES: [OH-].[K+].[I:3]I.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH:12]=2)[CH:7]=[CH:6]1>CN(C=O)C.O>[I:3][C:7]1[C:8]2[C:13](=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[NH:5][CH:6]=1
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(I)c[nH]c2c1)N1CCOCC1

Procedure:
Potassium hydroxide (422 mg, 7.543 mmol, 3.47 eq), iodine (1.103 g, 4.347 mmol, 2.0 eq) and (1H-indol-6-yl)(morpholino)methanone (500 mg, 2.173 mmol, 1.0 eq) in DMF (10 mL) were stirred at room temperature for 5 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated in vacuo. White solid. Yield: 600 mg (77% of theory)