Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:25][C:26]#[N:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.[C:31](#N)C.C(N(CC)CC)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(=O)(O)[O-].[Na+].CCOC(C)=O>[CH3:31][N:22]1[CH2:21][CH2:20][C:19]([CH2:25][C:26]#[N:27])([N:17]2[CH:18]=[C:14]([C:12]3[N:11]4[CH:28]=[CH:29][N:30]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)[CH:15]=[N:16]2)[CH2:24][CH2:23]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCNCC4)c3)n2)cn1
Reactant: CC#N
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCC(CC#N)(n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)CC1
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
2-(4-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-4-yl)acetonitrile hydrochloride (15.8 mg, 0.0318 mmol) was suspended in acetonitrile (318 μL, 0.0318 mmol). To this was added triethylamine (17.7 μL, 0.127 mmol) to freebase, followed by formaldehyde (25.8 mg, 0.318 mmol). After 30 minutes, NaBH(OAc)3 (33.7 mg, 0.159 mmol) was added. After stirring for 30 minutes, the reaction mixture was diluted in saturated sodium bicarbonate and EtOAc. The aqueous layer was back-extracted with DCM. The combined organic layer was washed with brine, dried with MgSO4, filtered and concentrated. Purification of the resulting crude material by reverse phase HPLC using a 0-100% acetonitrile/water gradient afforded 2-(1-methyl-4-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-4-yl)acetonitrile (2.0 mg, 16% yield). MS (apci) m/z=402.1 (M+H).
Reaction SMILES: [C:1]1([C@H:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:38]1([CH2:41][O:42][C:43]2[CH:44]=[C:45]([C@@H:53]([O:64][C:65]([C@H:67]3[NH:71][CH2:70][CH2:69][S:68]3)=[O:66])[CH2:54][C:55]3[C:60]([Cl:61])=[CH:59][N+:58]([O-:62])=[CH:57][C:56]=3[Cl:63])[CH:46]=[CH:47][C:48]=2[O:49][CH:50]([F:52])[F:51])[CH2:40][CH2:39]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:38]1([CH2:41][O:42][C:43]2[CH:44]=[C:45]([C@@H:53]([O:64][C:65]([C@H:67]3[N:71]([C:17](=[O:18])[C:16]4[CH:20]=[CH:21][C:13]([CH2:12][O:11][C:10]5[CH:22]=[CH:23][CH:24]=[C:8]([C@H:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[NH:25][C:26]([O:28][C@@H:29]6[CH:34]7[CH2:33][CH2:32][N:31]([CH2:36][CH2:35]7)[CH2:30]6)=[O:27])[CH:9]=5)=[CH:14][CH:15]=4)[CH2:70][CH2:69][S:68]3)=[O:66])[CH2:54][C:55]3[C:60]([Cl:61])=[CH:59][N+:58]([O-:62])=[CH:57][C:56]=3[Cl:63])[CH:46]=[CH:47][C:48]=2[O:49][CH:50]([F:52])[F:51])[CH2:40][CH2:39]1
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)N3CCS[C@H]3C(=O)O[C@@H](Cc3c(Cl)c[n+]([O-])cc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)cc2)c1)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
To a stirred solution of 4-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)benzoic acid (I17, 61 mg, 0.125 mmol) in DMF (2 mL) was added [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-thiazolidine-2-carboxylate hydrochloride (I5, 71 mg, 0.125 mmol) followed by DMAP (8 mg, 0.06 mmol) and EDC.HCl (48 mg, 0.25 mmol). The mixture was allowed to stir at room temperature for 18 h and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo. Purification was achieved by preparative HPLC to afford the title compound as a white solid (43 mg, 34%). 1H NMR (400 MHz, DMSO): δ 8.57 (s, 2 H), 8.23 (d, J=9.4 Hz, 1 H), 7.58-7.42 (m, 4 H), 7.37-6.87 (m, 12 H), 7.10 (t, J=74.4 Hz, 1 H), 6.08-5.97 (m, 1 H), 5.84 (d, J=9.1 Hz, 1 H), 5.58-5.48 (m, 1 H), 5.16 (s, 2 H), 4.60-4.53 (m, 1 H), 4.00-3.88 (m, 1 H), 3.88 (d, J=7.0 Hz, 2 H), 3.83-3.73 (m, 1 H), 3.55-2.92 (m, 5 H), 2.79-2.31 (m, 5 H), 1.93-1.13 (m, 6 H), 0.58-0.52 (m, 2 H), 0.32-0.26 (m, 2 H). LCMS (Method 1): [MH+]=1003 at 3.16 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1>O1CCOCC1.OS(O)(=O)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:5]([CH3:9])([CH3:6])[CH3:4])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of 4-bromo-2-fluorobenzoic acid (20.16 g, 92 mmol) in dioxane (90 mL) and conc. H2SO4 (5 mL) was cooled to 0° C., and then bubbled through with isobutene for 2 h. The reaction was allowed to gradually warm up to room temperature overnight. Solid NaHCO3 (40 g) was carefully added to the reaction and the mixture was stirred for 1 h. The mixture was concentrated, and then redissolved in water and ethyl acetate. The layers were separated. The aqueous phase was washed with ethyl acetate. The combined organics were washed with sat aq NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated. The resulting oily tert-butyl 4-bromo-2-fluorobenzoate was used without further purification. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.79-7.70 (m, 1H), 7.42-7.23 (m, 3H), 1.59 (s, 11H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C1COCC1>[N:23]1([CH2:22][CH2:21][NH:20][S:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Nc1ccc(S(=O)(=O)NCCN2CCOCC2)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
Diisopropylethylamine (0.09 ml, 0.5 mmol) was added in one portion to a stirred solution of 4-amino-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide (0.1 g, 0.35 mmol) in THF (3 ml) at room temperature. To this mixture was added acryloyl chloride (0.03 ml, 0.38 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue purified by Prep HPLC to give the title compound (6 mg, 5% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][CH2:14][CH2:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][S:18][C:17]1=[N:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[O:36][CH3:37])[CH2:9][C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:39]([NH2:41])[CH3:40].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>O.CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:13][CH2:14][CH2:15][N:16]1[C:20]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:19][S:18][C:17]1=[N:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[O:36][CH3:37])[CH2:9][C:10]([NH:41][CH2:39][CH3:40])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)CN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a mixture of the carboxylic acid compound (1.0 g) obtained in Example 327 (1), ethylamine hydrochloride (297 mg), 1-hydroxybenzotriazole monohydrate (418 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg) and N,N-dimethylformamide (7 ml) was added dropwise N,N-diisopropylethylamine (1.27 ml), and the mixture was stirred overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (1:1)] to give the title compound (929 mg) as foam. (2) N2-{3-[2-[(4-chloro-2-methoxyphenyl)imino]-4-(4-fluorophenyl)thiazol-3(2H)-yl]propyl}-N1-ethylglycinamide
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16](=[O:19])[CH2:17][CH3:18])=[C:4]([O:20][CH3:21])[CH:3]=1.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:32]=1)[C:27](O)=[O:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16](=[O:19])[CH2:17][CH3:18])[C:27](=[O:28])[C:26]2[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:32]=[C:24]([C:23]([F:38])([F:22])[F:37])[CH:25]=2)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: CCC(=O)CNc1cnccc1-c1ccc(F)cc1OC
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: CCC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from 1-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-butan-2-one and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 24 hours. The compound was purified by silica gel chromatography on a 5 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100), followed by a second chromatography using preparative HPLC (Gemini NX column) and a gradient of methanol:water (with 0.05% formic acid) (80:20 to 98:2). Colorless solid (10%). MS (ESI): m/z=530.130 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.[F-].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: c1nc[nH]n1
Reactant: COC(=O)C(=Cc1ccc(OC)cc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(c1ccccc1)C(c1ccc(OC)cc1)n1cncn1
Yield: 12.1 %

Procedure:
65 g (0.24 mole) of 3-(4-methoxyphenyl)-2-phenylacrylic acid methyl ester and 67.3 g (0.98 mole) of 1,2,4-triazole were heated under reflux in the presence of 1.1 g of tribenzo-(18)-crown-6 and 8.1 g of potassium fluoride in 1 liter of acetonitrile for 240 hours. The solvent was then distilled off in vacuo, 700 ml of water were added to the residue and the mixture was extracted three times with 250 ml of methylene chloride each time. The combined organic phases were dried over sodium sulphate and concentrated. The residue was dissolved in 200 ml of acetone. 12 g of 1,5-naphthalenedisulphonic acid in 50 ml of acetone were filtered in and the precipitate formed was filtered off. This precipitate was taken up in 150 ml of saturated sodium bicarbonate solution and the mixture was extracted twice by stirring with 250 ml of methylene chloride each time. The combined organic phases were washed with 100 ml of water, dried over sodium sulphate and concentrated. The residue was recrystallized from ethyl acetate. 9.8 g of 3-(4-methoxyphenyl)-2-phenyl-3-(1,2,4-triazol-1-yl)-propionic acid methyl ester of melting point 159°-161° C. were obtained.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](O)=[O:7])=[N+:2]=[N-:3].S(Cl)([Cl:13])=O>ClCCCl>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([Cl:13])=[O:7])=[N+:2]=[N-:3]
Reactant: CC(C)(CC(=O)O)N=[N+]=[N-]
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Temperature: 50 °C

Procedure:
To a stirred solution of 3-azido-3-methylbutanoic acid (10 g, 69.8 mmol) in anhydrous 1,2-dichloroethane (50 mL) was added thionyl chloride (10.0 mL, 140 mmol). The flask was fitted with a condenser and the reaction was heated in a 50° C. oil bath for 2 hours. The reaction was concentrated to a brownish-black suspension. The residue was vacuum distilled through a short path distillation apparatus. The forerun was discarded and the major fraction distilled at 66° C. at 18 mbar as a pale yellow liquid (9.66 g, 59.7 mmol, 85.6%). 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2H). 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 6H), 3.10 (s, 2H).
Reaction SMILES: C(OC(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(C5CCN(C(OC(C)(C)C)=O)C5)=NC=4)=CC=3)=CC=2)=CN=1)=O)(C)(C)C.[CH3:47][O:48][C:49](=[O:84])[NH:50][CH:51]([C:55]([N:57]1[CH:62]([C:63]2[NH:64][C:65]([C:68]3[CH:73]=[CH:72][C:71](B4OC(C)(C)C(C)(C)O4)=[CH:70][CH:69]=3)=[CH:66][N:67]=2)[CH:61]2[CH2:83][CH:58]1[CH2:59][CH2:60]2)=[O:56])[CH:52]([CH3:54])[CH3:53].[CH3:85][O:86][C:87](=[O:112])[NH:88][CH:89]([C:93]([N:95]1[CH2:99][CH2:98][CH2:97][CH:96]1[C:100]1[NH:101][C:102]([C:105]2[CH:110]=[CH:109][C:108](Br)=[CH:107][CH:106]=2)=[CH:103][N:104]=1)=[O:94])[CH:90]([CH3:92])[CH3:91].C(OC(N1CCCC1C1NC(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=CN=1)=O)(C)(C)C.C(OC(N1CCC(C2NC(C3C=CC(Br)=CC=3)=CN=2)C1)=O)(C)(C)C>>[CH3:85][O:86][C:87](=[O:112])[NH:88][CH:89]([C:93]([N:95]1[CH2:99][CH2:98][CH2:97][CH:96]1[C:100]1[NH:101][C:102]([C:105]2[CH:110]=[CH:109][C:108]([C:71]3[CH:70]=[CH:69][C:68]([C:65]4[NH:64][C:63]([CH:62]5[CH:61]6[CH2:83][CH:58]([CH2:59][CH2:60]6)[N:57]5[C:55](=[O:56])[CH:51]([NH:50][C:49]([O:48][CH3:47])=[O:84])[CH:52]([CH3:54])[CH3:53])=[N:67][CH:66]=4)=[CH:73][CH:72]=3)=[CH:107][CH:106]=2)=[CH:103][N:104]=1)=[O:94])[CH:90]([CH3:92])[CH3:91]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)C1
Agent: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5C6CCC(C6)N5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
Following the procedure used to prepare compound 2-(5-{4′-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester, except that [2-methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester and (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester were used instead of 2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H-NMR (300 MHz, CD3OD) δ 7.90-7.70 (m, 10H), 7.20-7.10 (m, 1H), 5.24 (t, 1H), 4.63 (s, 1H), 4.40-3.80 (m, 4H), 3.68 (s, 3H), 3.66 (s, 3H), 2.60-1.60 (m, 13H), 1.05-0.90 (m, 12H); m/z 765.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH:6]([CH3:8])[CH3:7].[P:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[P:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].[CH3:1][O:2][C:3](=[O:10])[CH:4]([P:11]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:18])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(Br)CC(C)C
Agent: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(CC(C)C)C(=O)OC
Temperature: 200 °C

Procedure:
2-Bromo-4-methyl-pentanoic acid methyl ester (193 g, 0.92M) and triethyl phosphite (330 ml, 1.84M) were heated to 150°. The reaction temperature was increased to 200° C. over 6 h and a distillate b.p. 37°-60° C. (80 g) collected with an air condenser. The residue was distilled under high vacuum to afford 2 fractions (a) mainly triethyl phosphite b.p. 40°-80° C. at 0.4 mm Hg and (b) 4-methyl-2-(diethyl phosphono)pentanoic acid methyl ester (188 g) b.p. 96°-100° C. at 0.4 mm Hg (Found: C, 47.6; H, 8.6.C11H23O5P+0.6H2O requires C, 47.7; H, 8.8%); δ(CDCl3) 0.9 (6H, dd, J=7 Hz, J=7 Hz, (CH3)2C); 1.04-2.10 (3H, m, CH2CH); 1.34 (6H, t, J=7 Hz, (CH2CH3)2); 3.09 (1H, ddd, J=23 Hz, J=10 Hz, J=4 Hz, CHP); 3.73 (3H, s, CH3O); 4.14 (4H, m, (CH2CH3)2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=O)=[CH:29]3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=[C:9]2[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[NH:11][C:10]2=[O:16])=[CH:29]3)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with (5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][C:5]([C:11]#[N:12])=[CH:4][C:3]1=2.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][N:6]1[C:7]2[CH2:8][CH2:9][CH2:10][C:2](=[O:1])[C:3]=2[CH:4]=[C:5]1[C:11]#[N:12]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc2c([nH]1)CCCC2=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1cc2c(n1Cc1ccc(Cl)c(Cl)c1)CCCC2=O
Yield: 91 %

Procedure:
4-Oxo4,5,6,7-tetrahydroindol-2-carbonitrile (5.5 g) (Estep, K. G.; Synthetic Communications, 1995, 25, 507-514) in DMF (100 mL) was stirred with 3,4-dichlorobenzyl chloride (5.86 g), potassium iodide (cat.) and potassium carbonate (5.5 g) overnight until reaction was complete. The mixture was poured onto ice and partitioned between water and methylene chloride. The organic phase was washed with brine and dried (MgSO4), and the solvents removed in vacuo, to afford a pale yellow solid. Trituration with ether afforded the title compound as a white solid (8.71 g, 91%), NMR d(CDCl3) 2.20 (2H, dt), 2.50 (2H, t), 2.78 (2H, t), 5.20 (2H, s) 6.95 (1H, dd), 7.20 (2H, m), 7.45 (1H, d); M/z (+) 321 (MH+), 319.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH:19](Br)[CH:18]([CH2:22][CH2:23][CH3:24])[CH2:17][O:16]2)=[CH:11][C:10]=1[F:25])C1C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.O.CC(OC)(C)C.[Pd]>[F:25][C:10]1[CH:11]=[C:12]([CH:15]2[CH2:20][CH2:19][CH:18]([CH2:22][CH2:23][CH3:24])[CH2:17][O:16]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CCCC1COC(c2ccc(OCc3ccccc3)c(F)c2)CC1Br
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O
Solvent: COC(C)(C)C
Product: CCCC1CCC(c2ccc(O)c(F)c2)OC1

Procedure:
123.0 g (0.30 mol) of 2-(4-benzyloxy-3-fluorophenyl)-4-bromo-5-propyltetrahydropyran are hydrogenated in toluene/water in the presence of Pd/C (5% of Pd) and 86.0 ml (0.60 mol) of triethylamine. The reaction solution is diluted with MTBE, and the organic phase is separated off. The aqueous phase is extracted with MTBE. The combined organic phases are washed with water and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is used directly for the following reaction.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]1([C:16]2[CH:17]=[C:18]([OH:23])[C:19](=[CH:21][CH:22]=2)[OH:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:10]1([C:16]2[CH:22]=[CH:21][C:19]3[O:20][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][O:23][C:18]=3[CH:17]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccc(-c2ccccc2)cc1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1COc2cc(-c3ccccc3)ccc2O1

Procedure:
46.1 g of ethyl 2,3-dibromopropionate was added slowly to a mixture of 30 g of 4-phenylcatechol, 66.2 g of potassium carbonate, and 250 ml of acetone. The mixture was refluxed for 18 hours, cooled and filtered. The solvent was evaporated from the filtrate under reduced pressure. The residue was extracted with hot cyclohexane. The extract was dried (MgSO4) and filtered. The solvent was evaporated from the filtrate under reduced pressure. The residue was taken up in hexane/methylene chloride. The solution was cooled. The resulting solid (7A) was separated and recrystallized from cyclohexane to give 7, mp: 103°-105° C.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN([CH:28]=[O:29])C1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>>[CH2:1]([O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:28]=[O:29])=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccccc1
Reactant: CN(C=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Reaction time: 1 h

Procedure:
Dodecyloxybenzene (2.48 g; 9.45 mmol) is dissolved in N-methylformanilide (195.17 g; 9.45 mmol). POCl3 (1.45 g; 159.33 g; 9.45 mmol) is added dropwise with ice-cooling. Stirring is carried out for 1 hour at 25° C., and then for 3 hours at 60° C. Pouring onto ice is then carried out and the pH is adjusted to 6 using sodium hydroxide solution. Extraction is then carried out with tert-butyl methyl ether (2×50 ml), and the combined organic phases are washed with aqueous NaHCO3 solution and dried over Na2SO4. After filtration, concentration to dryness by evaporation is carried out.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:4].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>N1C=CC=CC=1>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: Nc1nccs1
Reactant: O=C(N1CCCC1c1ccc(S(=O)(=O)Cl)cc1)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(N1CCCC1c1ccc(S(=O)(=O)Nc2nccs2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 31.9 %

Procedure:
Prepared using general procedure 37. Under an N2 atmosphere, a mixture of the 4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzene-1-sulfonyl chloride (1.1 g, 5.8 mmol), 2-aminothiazole (0.58 g, 5.8 mmol), and pyridine (4.0 mL) was stirred at RT for 19 h. The crude product was purified via silica gel chromatography using 3% MeOH in CH2Cl2. The resulting oil was taken up in a 2:1 mixture of CH2Cl2:Et2O (12 mL) and cooled to 0° C. for 20 minutes. The formed precipitate was filtered off and dried under vacuum to obtain N-(thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzene-sulfonamide as a white solid (750 mg, 32%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=405.1; tR=2.68 min.