Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:6].C([C:28]1[C:29]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)#N>>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([S:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:2]([NH:1][C:39]3[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:29]=4[N:35]=[CH:36][N:37]=3)[CH:3]=2)=[CH:9][CH:10]=1
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: Cc1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(O)cc3)ncnc2n1
Yield: 51 %

Procedure:
The product of Example 28A was reacted with the product of Example 9B using the procedure of Example 22C substituting the product of Example 28A for the product of Example 22B and substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (24 mg, 51%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.68 (s, 3 H) 6.85 (d, J=8.46 Hz, 2 H) 6.89-7.00 (m, 1 H) 7.31 (d, J=8.82 Hz, 2 H) 7.45-7.64 (m, 3 H) 7.67-7.88 (m, 3 H) 7.97 (s, 1 H) 8.58 (s, 1 H) 8.70-8.92 (m, 1 H) 9.96 (s, 1 H) 10.19 (s, 1 H) 10.29 (s, 1 H); MS (ESI+) m/z 558/560 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]3[N:20]=[CH:21][CH:22]=[CH:23][C:11]=3[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].O>CN(C)C=O>[O:38]=[C:29]1[C:30]2[C:31](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:33])[N:28]1[CH2:27][CH2:26][CH2:25][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:10][C:11]2[CH:23]=[CH:22][CH:21]=[N:20][C:12]1=2
Reactant: c1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.9 %

Procedure:
To a stirred suspension of 0.56 g (0.023 mole) of sodium hydride in 25 ml of anhydrous dimethylformamide was added, portionwise, 5.0 g (0.0184 mole) of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The reaction mixture was warmed to 80°±2° C. for 1 hr and cooled to room temperature. A solution of 5.55 g (0.020 mole) of N-(3-bromopropyl)phthalimide in 10 ml of anhydrous dimethylformamide was added dropwise and after stirring for 16 hr the reaction mixture was poured into 650 ml of water and stirred for 30 min. The yellow solid was collected by filtration and recrystallized three times from isopropyl alcohol to give 3.7 g of product, m.p. 170°-172° C.
Reaction SMILES: C(C1C=CC(C2C=C(F)SC=2CO)=CC=1)C.OC1C=CC(CCC(OCC)=O)=C(F)C=1F.[F:33][C:34]1[S:38][C:37]([CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]([O:51]CC)=[O:50])=[C:43]([F:54])[C:42]=2[F:55])=[C:36]([C:56]2[CH:61]=[CH:60][C:59]([CH2:62][CH3:63])=[CH:58][CH:57]=2)[CH:35]=1>>[CH2:62]([C:59]1[CH:58]=[CH:57][C:56]([C:36]2[CH:35]=[C:34]([F:33])[S:38][C:37]=2[CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[C:43]([F:54])[C:42]=2[F:55])=[CH:61][CH:60]=1)[CH3:63]
Reactant: CCOC(=O)CCc1ccc(OCc2sc(F)cc2-c2ccc(CC)cc2)c(F)c1F
Agent: CCOC(=O)CCc1ccc(O)c(F)c1F
Agent: CCc1ccc(-c2cc(F)sc2CO)cc1
Product: CCc1ccc(-c2cc(F)sc2COc2ccc(CCC(=O)O)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 205 by coupling of [3-(4-ethylphenyl)-5-fluorothiophen-2-yl]methanol and ethyl 3-(4-hydroxy-2,3-difluorophenyl)propanoate followed by hydrolysis of ethyl 3-(4-((5-fluoro-3-(4-ethylphenyl)thiophen-2-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.25-7.35 (m, 2H), 6.93 (t, J=8.1 Hz, 1H), 6.73 (t, J=8.1 Hz, 1H), 6.65 (s, 1H), 5.13 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.57-2.72 (m, 4H), 1.26 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H19F3O3S, 419.1 (M−H). found 419.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:56])[N:27]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:28]([CH2:31][C@H:32]([O:34][C:35](=[O:49])[C@@H:36]([NH:38]C(OCC3C=CC=CC=3)=O)[CH3:37])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:57]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:56])[N:27]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:28]([CH2:31][C@H:32]([O:34][C:35](=[O:49])[C@@H:36]([NH2:38])[CH3:37])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:57]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)N)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)—((R)-1-(4-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl-carbamoyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazol-1-yl)propan-2-yl)2-(benzyloxy-carbonylamino)propanoate (200 mg, 0.257 mmol) in a mixture of EtOAc (15 mL) and MeOH (10 mL) was added catalytic amount of Pd/C (10%, ˜55% w/w water content, 20 mg) under N2 atmosphere. The suspension was degassed under vacuum and then purged with H2. The reaction mixture was stirred at rt for 20 minutes under H2 balloon. The mixture was filtered and the residue was washed with MeOH (5 mL×3). The filtrate used for the next step immediately.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:35]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([O-:37])=[O:36].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][CH2:22][C:23]([O:25][CH2:42][C:41]2[CH:44]=[CH:45][C:38]([N+:35]([O-:37])=[O:36])=[CH:39][CH:40]=2)=[O:24])=[O:11])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(=O)S[C@H]1C[C@@H](CCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)S[C@H]1C[C@@H](CCC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
(2R,4S)-1-p-Nitrobenzyloxycarbonyl-2-(2-carboxyethyl)-4-acetylthiopyrrolidine (323 mg) was dissolved in 3.3 ml of dry dimethylformamide, and 150 mg of triethylamine and 324 mg of p-nitrobenzyl bromide were added thereto, followed by stirring at room temperature for 3.5 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate, washed successively with a saturated sodium bicarbonate solution, water, dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and distilled off to remove the solvent. The residue was purified by silica gel column chromatography to obtain (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-(2-p-nitrobenzyloxycarbonylethyl)-4-acetylthiopyrrolidine.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)(OCC)=O)C.[H-].[Na+].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH:32]=O>C1COCC1>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1/[CH:32]=[CH:9]/[C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of methyl 4-[(diethoxyphosphoryl)methyl]benzoate (916 mg, 3.20 mmol; see Preparation 4(i) above) in THF (20 mL, dry) under nitrogen atmosphere was added a sodium hydride (520 mg, 60% dispersion in oil, 13.00 mmol) at 0° C. 2-Naphthaldehyde (500 mg, 3.20 mmol) was dissolved in THF (10 mL, dry) then added dropwise to the reaction mixture at 0° C. under N2 and the reaction mixture stirred at room temperature for 1 h followed by quenching with water. The pH level of the mixture was adjusted to pH 4 by the dropwise addition of HCl(conc.) with stirring at 0° C. TLC analysis showed that it was the required product (282 mg). Extraction of the water layer with ethyl acetate followed by drying (MgSO4) gave the sub-title compound (total amount 846 mg, 92%), m.p.=195-198° C.
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][C:11]([CH3:22])([OH:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>>[I:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]2([CH3:22])[O:21][C:2]3=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]3[CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(O)(COc1ccc(I)cc1)Cn1cc([N+](=O)[O-])nc1Br
Agent: [H-]
Agent: [Na+]
Product: CC1(COc2ccc(I)cc2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 92 %

Procedure:
Ring closure of alcohol 99 with NaH as in Example 2A for 75 min, followed by chromatography of the product on silica gel, eluting with CH2Cl2, gave 2-[(4-iodophenoxy)methyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (100) (92%) as a cream solid: mp (MeOH/CH2Cl2/hexane) 181-183° C.; 1H NMR (CDCl3) δ 7.57 (dt, J=9.0, 2.7 Hz, 2H), 7.54 (s, 1H), 6.63 (dt, J=9.0, 2.7 Hz, 2H), 4.46 (d, J=10.2 Hz, 1H), 4.20 (d, J=10.1 Hz, 1H), 4.05 (d, J=9.9 Hz, 1H), 4.03 (d, J=10.1 Hz, 1H), 1.78 (s, 3H). Anal. (C13H12IN3O4) C, H, N.
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(N)c(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(N)c(C#C[Si](C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Into a mixture of 4-fluoro-2-iodo-5-methylaniline (12.0 g, 47.8 mmol, plus ca. 10% of the undesired isomer), PdCl2(PPh3)2 (1.68 g, 2.39 mmol) and copper(I) iodide (0.455 g, 2.39 mmol) in triethylamine (125 mL) at 0° C. was added trimethylsilylacetylene (5.15 g, 52.6 mmol) dropwise. The mixture was warmed to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in ethyl ether and filtered. The filtrate was evaporated and purified via flash chromatography with 5-35% ethyl acetate in hexane to give 4-fluoro-5-methyl-2-((trimethylsilyl)ethynyl)aniline (10.3 g, 97%), which contained ˜10% of the undesired isomer (4-fluoro-3-methyl-2-((trimethylsilyl)ethynyl)aniline).
Reaction SMILES: C1([Li])C=CC=CC=1.[CH3:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[N:11][C:10]=1[CH3:17].[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CCOCC>[OH:25][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][C:10]1[C:9]([CH3:8])=[N:14][C:13]([CH3:15])=[C:12]([CH3:16])[N:11]=1
Reactant: Cc1nc(C)c(C)nc1C
Reactant: O=Cc1ccccc1
Agent: [Li]c1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1nc(C)c(CC(O)c2ccccc2)nc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of phenyllithium in benzene-ether (90 milliliters, 0.095 mole) was diluted with 100 milliliters anhydrous ether and cooled to 0° C. A solution of 13.6 grams tetramethylpyrazine (0.1 mole) in 50 milliliters ether was added slowly to the phenyllithium solution. The reaction mixture was stirred at room temperature for 2 hours and heated under reflux for 1 hour. The mixture was allowed to cool to room temperature and a solution of 10 grams of freshly distilled benzaldehyde (0.1 mole) in 50 milliliters of ether was added dropwise. The mixture was stirred at room temperature for an additional 1.5 hours and cooled to 0° C. Water was added, and the organic phase was separated and washed three times with water. The recovered water extracts were washed with methylene chloride.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Cl:10][C:11]1[C:12]([F:20])=[CH:13][C:14]([F:19])=[C:15]([CH:18]=1)[CH2:16][NH2:17]>CCOC(C)=O>[Cl:10][C:11]1[C:12]([F:20])=[CH:13][C:14]([F:19])=[C:15]([CH:18]=1)[CH2:16][NH:17][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: NCc1cc(Cl)c(F)cc1F
Reactant: COC(=O)C(OC)OC
Solvent: CCOC(C)=O
Product: COC(OC)C(=O)NCc1cc(Cl)c(F)cc1F
Temperature: 80 °C

Procedure:
A mixture of methyl dimethoxyacetate (1.45 g, 10.7 mmol) and 5-chloro-2,4-difluorobenzylamine (1.78 g, 10.0 mmol) in a sealed tube was heated at 80° C. for 20 h. After that time, the mixture was diluted with EtOAc (20 ml), washed with HCl (2 N, 10 ml), saturated Na2CO3 (10 ml), H2O (10 ml) and brine (10 ml), and dried over MgSO4. After concentrated in vacuo, the title compound was obtained as a brown oil. 1H NMR (400 MHz, CDCl3): δ=3.41 (s, 6H), 4.46 (d, J=6.4 Hz, 2H), 4.74 (s, 1H), 6.92 (t, J=8.8 Hz, 1H), 6.93 (brs, 1H), 7.41 (t, J=8.0 Hz, 1H). MS(ES+): m/z=280.03/282.01 (95/57) [MH+]. HPLC: tR=3.02 min (polar—5 min, ZQ3).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10](Br)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1.[F-].[Cs+]>O1CCOCC1.C(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C1C=C(Br)C(=O)N1Cc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(C2=CC(=O)N(Cc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromomaleic anhydride (1 g, 5.7 mmol) and benzyl amine (0.7 mL, 6.8 mmol) in acetic acid (15 mL) was warmed to 50° C. and stirred overnight. The reaction was then cooled to room temperature, diluted with CH2Cl2 (50 mL) and washed with NaHCO3 (3×25 mL) and brine (25 mL). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified using gradient flash chromatography (0-100% ethyl acetate in pet ether) to provide 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (18). 1H NMR (400 MHz, CDCl3) δ 4.71 (s, 2H), 6.87 (s, 2H), 7.26-7.37 (m, 5H). A stirred solution of 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (0.26 g, 1.0 mmol) and p-tolylboronic acid (0.16 g, 1.2 mmol) in dioxane (10 mL) was degassed with a stream of nitrogen for 10 minutes before being treated with CsF (0.39 g, 2.6 mmol) and C12Pd(dppf).CH2Cl2 (0.05 g, 0.06 mmol). The reaction was stirred at room temperature for 1 h then warmed to 40° C. for 1 h. The mixture was then cooled, diluted with CH2Cl2 (30 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified using gradient flash chromatography (0-10% ethyl acetate in pet ether) to provide the title compound 15.
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH2:13]([O:15][P:16]([O-:20])[O:17][CH2:18][CH3:19])[CH3:14].[C:21]1(=[O:27])[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]1.Cl>ClCCl>[CH2:13]([O:15][P:16]([CH:23]1[CH2:24][CH2:25][CH2:26][C:21](=[O:27])[CH2:22]1)(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]
Reactant: CCOP([O-])OCC
Reactant: O=C1C=CCCC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1CCCC(=O)C1
Reaction time: 1 h
Yield: 95 %

Procedure:
0.52 mmol trimethylsilyltriflate is added dropwise to 11.4 mmol diethylphosphite and 12.4 mmol N,O-bis-(trimethylsilyl) acetamide in 5 ml dichlormethane at 0° C. . After 30 minutes of stirring at the same temperature 0.52 mmol 2-cyclohexen-1-one are added dropwise thereto and is stirred for 1 h. The enolsilane intermediate product is hydrolized by 3 ml 1 n HCl during 3 hours of stirring. The organic phase is separated, dried over magnesiumsulfate and concentrated. The raw product can be chromatographed on SiO2 and after concentration of the desired fractions results in 3-oxo-cyclohexylphosphonic acid diethylester 2(a) in a 95% yield.
Reaction SMILES: [Al](C)(C)C.C(O[C:8]([C:10]1[C:15]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[C:12]([CH:23]2[CH2:25][CH2:24]2)[N:11]=1)=[O:9])C.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=1>>[CH3:32][N:29]1[CH:30]=[CH:31][C:27]([NH:26][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH:23]3[CH2:24][CH2:25]3)[N:11]=2)=[O:9])=[N:28]1
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1nc(C2CC2)ccc1Nc1cccnc1
Agent: C[Al](C)C
Product: Cn1ccc(NC(=O)c2nc(C3CC3)ccc2Nc2cccnc2)n1

Procedure:
The Al(Me)3-catalyzed reaction of 6-Cyclopropyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid ethyl ester and 3-Amino-1-methylpyrazole in accordance with the general method of Example 78, step 2 yielded the title compound as a light yellow cristalline solid, MS (ISP): m/e=335.4 (M+H+).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:21].[Cl:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]([N:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)ncn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1cc(N2CCNCC2)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 200.4 %

Procedure:
Ethyl acetate saturated with gaseous HCl was added to a solution of 1-(tert-butoxycarbonyl)-4-(6-chloro-pyrimidin-4-yl)piperazine (16.80 g) in ethyl acetate (50 ml) and the resulting suspension stirred at ambient temperature for 3 hours. Solvent was evaporated to give (6-chloro-pyrimidin-4-yl)piperazine hydrochloride (13.25 g) as a cream solid.
Reaction SMILES: [I-].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCCC.C[O-].[Na+].C(=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCCCCC.C(OC([N:74]1[CH2:78][CH2:77][CH:76]([CH:79]=O)[CH2:75]1)=O)(C)(C)C>CN(C=O)C.C(C(C)=O)C>[CH2:79]([CH:76]1[CH2:77][CH2:78][NH:74][CH2:75]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCl
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Agent: CCCCCCC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCCCCCCCC1CCNC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 0.15 mol. of anhydrous sodium iodide and 150 ml. of dry methyl ethyl ketone is heated for 30 minutes at 80°, 0.1 mol of 1-chloroheptane is added, and heating is continued for 10 hours with periodic shaking. The cooled solution is filtered and most of the solvent is distilled off. The residue is diluted with 150 ml. of benzene, the solution is washed with water, 5% sodium thiosulfate, water, and dried over magnesium sulfate. The filtrate solution is concentrated to 100 ml., 0.12 mol. of triphenyl phosphine is added and the mixture is heated for 10 hours at 80°. The benzene is distilled off and the residue is triturated with ether, filtered and dried. A solution of 25 mmoles of this heptyltriphenyl phosphonium iodide in 40 ml. of dried DMF is mixed rapidly with 20 mmoles of sodium methoxide and the mixture is stirred for one hour at room temperature. The solution of heptylidenetriphenyl phosphorane is cooled with ice water and mixed with a solution of the 15 mmoles of the 1-(t-butoxycarbonyl)-3-pyrrolidinecarboxaldehyde obtained in step B, dissolved in 10 ml. of DMF and the mixture is stirred at 20° for 20 hours. After dilution with water, the desired 1-(t-butoxycarbonyl)-3-(1-octenyl)pyrrolidine is extracted with ethyl acetate. The ethyl acetate extract is concentrated to dryness in vacuo and the residue is hydrogenated in the presence of 10% palladium on charcoal, then treated with trifluoroacetic acid as in step E of the same example to obtain 3-octylpyrrolidine.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH:21]([CH3:23])[CH3:22])=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[CH:21]([C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[S:10][C:6]=1[C:4]([OH:5])=[O:3])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Temperature: 70 °C

Procedure:
To a solution of 4-isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester (0.62 g, 1.80 mmol) in THF (10 mL) is added 5M NaOH (3.5 mL, 17.50 mmol). The mixture is heated at 70° C. for 12 h. Upon cooling to RT, the mixture is acidified with 5M HCl and extracted with EtOAc. The organics are washed with water and brine, and dried with MgSO4. After concentration, the title compound is obtained (0.46 g, 81%). The material is used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.Cl.[NH2:14][C:15]1[CH:16]=[C:17]2[C:30](=[CH:31][CH:32]=1)[CH2:29][C:19]1([C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]1=[O:28])[CH2:18]2>CC(O)C>[O:28]=[C:20]1[NH:21][C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:27]2[C:19]21[CH2:18][C:17]1[C:30](=[CH:31][CH:32]=[C:15]([NH:14][C:2]3[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=3)[CH:16]=1)[CH2:29]2
Reactant: CCOC(=O)c1cc(Cl)ncn1
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Temperature: 25 °C

Procedure:
0.10 g (0.55 mmol) ethyl 6-chloropyrimidine-4-carboxylate and 13 μL (50 μmol) 4M HCl were added to 0.16 g (0.60 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one in 1.0 mL 2-propanol. The reaction mixture was refluxed for 2 h, then cooled to RT and the resulting solid was filtered off and dried.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[K+].[K+]>ClCCl.O>[Cl:1][C:2]1[C:3]([CH2:4][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([Cl:11])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: C1CCNC1
Reactant: O=Cc1c(Cl)ccc(O)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Cl)c(CN2CCCC2)c1Cl
Yield: 72.9 %

Procedure:
A solution of intermediate 22, 2,6-Dichloro-3-hydroxybenzaldehyde (5.00 g, 26.18 mmol) in 5 mL of dichloromethane was added to a mixture of pyrrolidine (2.75 mL, 32.72 mmol) and sodium triacetoxyborohydride (6.94 g, 32.72 mmol) in dichloromethane (45 mL) under stirring. The reaction mixture was stirred for 16 h at room temperature. Water (20 mL) and saturated K2CO3 (5 mL) were added, and the layers were separated. The water layer was subjected to extraction with CHCl3 (2×50 mL). The combined organic layers were washed with water (30 mL), brine, dried with Na2SO4, and evaporated. The residue was purified by chromatography (silica gel, 63/100 μm, 50 g, CHCl3/MeOH 100:0→80:20). Fractions containing the target compound were evaporated. The residue was crystallized from ether to furnish the title compound (4.7 g, 73%) as white crystals. LCMS data: 246 and 248 (M+H)+ (calculated for C11H13Cl2NO 246.14). 1H NMR data (DMSO-d6): 10.47 (br.s, 1H, OH); 7.19 (d, 1H, J=9 Hz, Ar—H); 6.89 (d, 1H, J=9 Hz, Ar—H); 3.78 (s, 2H, CH2Ar); 2.50-2.56 (m, 4H, CH2NCH2); 1.60-1.68 (m, 4H, CH2CH2).