Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:27]=[CH:26][C:16]([C:17]([O:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[O:18])=[CH:15][C:14]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[Cl:37][C:38]1[CH:39]=[N+:40]([O-:63])[CH:41]=[C:42]([Cl:62])[C:43]=1[CH2:44][C@@H:45]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:56])[F:55])=[C:49]([O:57][CH2:58][CH:59]2[CH2:61][CH2:60]2)[CH:48]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:27]=[CH:26][C:16]([C:17]([O:19][C:20]([CH3:25])([CH3:24])[C:21]([O:23][C@H:45]([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:55])[F:56])=[C:49]([O:57][CH2:58][CH:59]3[CH2:60][CH2:61]3)[CH:48]=2)[CH2:44][C:43]2[C:42]([Cl:62])=[CH:41][N+:40]([O-:63])=[CH:39][C:38]=2[Cl:37])=[O:22])=[O:18])=[CH:15][C:14]=1[O:28][CH2:29][CH:30]1[CH2:31][CH2:32]1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OC(C)(C)C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OC(C)(C)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.2 %

Procedure:
To a mixture of 2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)-2-methylpropanoic acid (300 mg, 0.636 mmol) and EDC (366 mg, 1.909 mmol) in dry DCM (10 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (267 mg, 0.636 mmol) and DMAP (78 mg, 0.636 mmol) were added, and the resulting solution was stirred at RT for 2 days. The solvent was evaporated and the residue was portioned between ethyl acetate and water; the organic phase was washed with 0.5N HCl, aqueous sat. NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH/32% NH4OH=95/5/0.5) to give (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoyloxy)-2-methylpropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide as a white powder (168 mg, 0.192 mmol, 30.2% yield, MS/ESI+873.4 [MH]+).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH3+:10])[C:6]([CH3:9])([CH3:8])[CH3:7].C(O[BH-](O[C:22](=O)[CH3:23])OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:4]([NH:10][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:5][CH2:6][CH2:7][CH:22]=[CH2:23]
Reactant: COC(=O)[C@@H]([NH3+])C(C)(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCCCCN[C@H](C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Hex-5-enal 98 (obtained from hex-5-en-1-ol via a PCC oxidation) (0.95 eq.) was added at RT to a 0.11 M solution of (2S)-1-methoxy-3,3-dimethyl-1-oxobutan-2-aminium chloride (1.0 eq.) and TEA (1.0 eq.) in DCE. Sodium triacetoxyborohydride (1.0 eq.) was added in one portion and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM/saturated aqueous NaHCO3. The phases were separated; the organic layer was washed with brine, dried (Na2SO4) and filtered though a short path of silica gel (PE:EtOAc=9:1) to afford the title compound 99 as a pale yellow liquid (72%). 1H NMR (300 MHz, CDCl3, 300 K) δ 5.89-5.71 (m, 1H), 5.07-4.88 (m, 2H), 3.71 (s, 3H), 2.88 (s, 1H), 2.62-2.48 (m, 1H), 2.45-2.31 (m, 1H), 2.13-1.98 (m, 2H), 1.67-1.54 (m, 1H), 1.53-1.35 (m, 4H), 0.95 (s, 9H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[CH:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][S:2][C:3]1[C:4]2[C:5]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)=[C:6]([Br:27])[NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1cccc2[nH]cc(Cc3ccc(Cl)cc3)c12
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1cccc2[nH]c(Br)c(Cc3ccc(Cl)cc3)c12
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of the indole of Step 6 (700 mg, 2.4 mmol) in CCl4 (15 mL) was added NBS (475 mg, 2.7 mmol). The reaction mixture was heated to 50° C. and stirred for 20 minutes. The resulting suspension was filtered on SiO2 pad eluted with 50% EtOAc in hexanes and concentrated. The title compound was obtained in quantitative yield as a brownish solid foam and used as such.
Reaction SMILES: [C:1]([C:3]1[CH:48]=[CH:47][C:6]([CH2:7][C@@:8]2([CH3:46])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22]([NH:24][C:25]5([C:28]6[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=6)[C:31]([OH:33])=O)[CH2:27][CH2:26]5)=[O:23])[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=3)[C:9]2=[O:45])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:73][C:74]([CH3:78])([CH3:77])[CH2:75][OH:76]>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@:8]2([CH3:46])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22](=[O:23])[NH:24][C:25]5([C:28]6[CH:29]=[C:30]([C:31](=[O:33])[NH:73][C:74]([CH3:78])([CH3:77])[CH2:75][OH:76])[CH:34]=[CH:35][N:36]=6)[CH2:27][CH2:26]5)[CH2:20][CH2:21]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=3)[C:9]2=[O:45])=[CH:47][CH:48]=1)#[N:2]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(C(=O)O)ccn5)CC4)CC3)n21
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)c1ccnc(C2(NC(=O)C3(NC(=O)c4cnc5n4[C@](C)(Cc4ccc(C#N)cc4)C(=O)N5c4cc(Cl)cc(Cl)c4)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
To a stirred solution of 2-{1-[(1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-amino]-cyclopropyl}-isonicotinic acid (30 mg, 0.044 mmol), in 3 mL DMF was added HATU (25 mg, 0.66 mmol) diisopropylethylamine (0.3 mL) and 2-amino-2-methyl-propan-1-ol (5.8 mg, 0.66 mmol). The solution was allowed to stir at room temperature overnight (18 h). The reaction was diluted with water (5 mL), then extracted with a 5% methanol/dichloromethane solution (3×10 mL). The organic layers were combined, dried (MgSO4) and concentrated. The resulting oil was purified by reversed phase HPLC to afford 28 mg of the title compound, m/z 755.7.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:14]([SH:17])=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[C:3]2[N:4]([C:14]([S:17][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: Brc1ccc2ncccc2c1
Reactant: Cn1cc(-c2cc(F)c3nnc(S)n3c2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(F)c3nnc(Sc4ccc5ncccc5c4)n3c2)cn1
Temperature: 120 °C
Yield: 33.2 %

Procedure:
A mixture of Intermediate F (40 mg, 0.160 mmol), 6-bromoquinoline (33.4 mg, 0.160 mmol), xantphos (18.57 mg, 0.032 mmol), Pd2(dba)3 (14.69 mg, 0.016 mmol) and DIPEA (0.111 ml, 0.642 mmol) in DMF (5 ml) was bubbled with N2 for 15 min and then was heated to 120° C. for 5 h under MW radiation. The solvent was removed under reduced pressure. The residue was purified with by silica gel chromatography eluted with DCM/MeOH (from 100% to 90%) to afford the title compound as a brownish solid (20 mg, 29.8% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.87 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.29 (d, 1H), 8.04 (m, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.53 (m, 1H), 3.84 (s, 3H). LCMS (method B): [M+H]+=377, tR=1.95 min.
Reaction SMILES: [C:1]([OH:27])(=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:28]O>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[C:1]([O:27][CH3:28])(=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CO
Reactant: CCCCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Temperature: 25 °C

Procedure:
10,12-pentacosadiynoic acid (10 gm, GFS Chemicals) was dissolved in a solution containing 10 ml methanol (HPLC grade) and 10 ml chloroform (HPLC grade). The solution was stirred at room temperature and 10 drops of neat sulfuric acid was added drop wise. The solution was warmed to 100° F. for 2 hour. The reaction mixture was purified using column chromatography. The product (MePDA) was dried using a rotovap and the material stored in a chloroform solution. The solid form of MePDA was very unstable to polymerization and therefore kept dissolved in organic solutions.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=O)[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9][C:4]=2[CH:3]=1>C(O)(=O)C.CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:6][CH2:7][CH:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2ccc(O)cc2O1
Yield: 96 %

Procedure:
A solution of ethyl 7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate (19.0 g, 0.081 mol) in acetic acid is hydrogenated over 10% Pd/C (4.5 g) at 50 psi H2 for 16 hr at ambient temperatures. The catalyst is removed by filtration and the filtrate is concentrated in vacuo to give a residue. The residue is dissolved in EtOAc, washed with saturated NaHCO3, dried over Na2SO4 and concentrated in vacuo to give a solid residue. Crystallization of the solid from CCl4 affords the title compound as an off-white solid, 17.2 g (96% yield), mp 78-80° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([Br:21])[CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1>O1CCCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)([C:9]2[CH:10]=[C:11]3[C:6](=[C:7]([Br:21])[CH:8]=2)[N:5]=[C:4]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=[C:2]3[Br:1])[OH:13])=[CH:19][CH:18]=1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)cc(Br)c2n1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4,8-dibromo-2-(tert-butoxy)-6-[(4-chlorophenyl)carbonyl]quinoline (440 mg, 0.88 mmol, 1.00 equip) in tetrahydrofuran (30 mL). To the resulting mixture was then added (4-chlorophenyl)magnesium bromide (2.67 mL, 3.00 equip, 1 M) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of saturated sodium bicarbonate (50 mL). The resulting solution was extracted with ethyl acetate (100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to yield bis(4-chlorophenyl)[4,8-dibromo-2-(tert-butoxy)quinolin-6-yl]methanol as a yellow solid. LCMS (ES, m/z) 610 [M+H]+
Reaction SMILES: [C:1]1([C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[C:14]([C:24]#[N:25])=[C:13]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1C[O:37]CC1>>[C:1]1([C:11]2[C:23]3[C:22](=[O:37])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[C:14]([C:24]#[N:25])=[C:13]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccc3ccccc23)c2c1-c1ccccc1C2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2cccc3ccccc23)c2c1-c1ccccc1C2=O
Temperature: 2.5 °C

Procedure:
A solution of 1-(naphthalen-1-yl)-3-(piperidin-1-yl)-9H-fluorene-4-carbonitrile (400 mg) in THF was added sodium hydride (39 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Yellow solid; mp 180-182° C.; ESIMS 415 (M-+1); IR (KBr) 2213 (CN), 1707 cm−1 (CO); 13C NMR (75.53 MHz, CDCl3): δ 22.65, 24.68, 51.57, 95.45, 115.96, 118.89, 121.27, 122.49, 122.80, 123.78, 123.92, 124.68, 124.78, 125.04, 127.22, 127.57, 129.35, 130.02, 132.05, 133.10, 133.93, 134.13, 139.41, 143.51, 149.06, 158.86, 187.99.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=O)#[N:2].P(Cl)(Cl)(Cl)=O.N>C(Cl)(Cl)Cl>[CH:7]1[N:6]=[C:4]([CH2:3][C:1]#[N:2])[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=12
Reactant: N#CCC(=O)NCc1ccccn1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#CCc1ncc2ccccn12
Temperature: 0 °C
Yield: 35.9 %

Procedure:
2-Cyano-N-(2-pyridylmethyl)acetamide (15.51 g) was dissolved in chloroform (80 ml). To the solution was added phosphorus oxychloride (40 ml), which was refluxed for 4 hours. The reaction mixture was added to ice-water in limited amounts, to which was added a 25% aqueous ammonia (140 ml) to neutralize, which was then shaken. The aqueous layer was subjected to extraction with ethyl acetate (150 ml) twice. The organic layers were combined and dried over anhydrous magnesium sulfate, followed by concentration. The concentrate was purified by means of a column chromatography (carrier: silica gel, 250 g, developing solvent: ethyl acetate) to afford the title compound (5.00 g).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[Cl:22][C:23]1[C:28](O)=[CH:27][C:26]([C:30]2[C:34]([CH3:35])=[C:33]([S:36][CH3:37])[N:32]([CH3:38])[N:31]=2)=[C:25]([F:39])[CH:24]=1>O1CCOCC1>[Cl:22][C:23]1[C:28]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[CH:27][C:26]([C:30]2[C:34]([CH3:35])=[C:33]([S:36][CH3:37])[N:32]([CH3:38])[N:31]=2)=[C:25]([F:39])[CH:24]=1
Reactant: CSc1c(C)c(-c2cc(O)c(Cl)cc2F)nn1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CSc1c(C)c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)cc2F)nn1C
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
65 ml (0.8 mol) of pyridine and then 80 ml (0.48 mol) of trifluoromethanesulfonic acid anhydride are added dropwise at 0-5° C. to a solution of 129 g (0.3 mol) of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-5-(methylthio)-1-methyl-[1H]-pyrazole (approx. 70%) (Example P9) in 1.2 liters of 1,4-dioxane. After being stirred for 30 minutes at 0-5° C. and then at 22° C. overnight, the reaction mixture is concentrated to approximately 1/3 of its original volume by evaporation, poured into a mixture of ice, water and hydrochloric acid, extracted with MTBE, washed with water and concentrated by evaporation. After purification of the crude product by silica gel chromatography, 87.7 g (70% of the theoretical yield) of the desired compound are isolated in the form of crystals having a melting point of 54-56° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[OH:23]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:7]([C:6]2[CH:5]=[C:4]([CH3:10])[S:3][C:2]=2[Br:1])=[O:9])=[C:17]([OH:23])[CH:18]=1
Reactant: Nc1ccc(F)cc1O
Reactant: Cc1cc(C(=O)O)c(Br)s1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2ccc(F)cc2O)c(Br)s1

Procedure:
In the same manner as in Starting Material Synthesis Example 67 and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-5-fluorophenol, N-(4-fluoro-2-hydroxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:16]=1[NH2:17])[CH3:14].C(O)=O>CCCCCCC>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:16]=1[N:17]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11])[CH3:14]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: CCc1cccc(CC)c1N
Solvent: O=CO
Solvent: CCCCCCC
Product: CCc1cccc(CC)c1N=C(C)c1cccc(C(C)=O)n1
Yield: 41.6 %

Procedure:
10.35 g of 2,6-diacetylpyridine (0.0634 mol), 7.10 g of 2,6-diethylaniline (0.0476 mol) and 2 ml of formic acid were stirred in 300 ml of heptane at room temperature for 71 h. The insoluble solid was filtered off (11.10 g) and dissolved in 150 ml of toluene and the solution was extracted with 10 ml of a saturated Na2CO3 solution. The toluene phase was dried over Na2SO4 and filtered and the solvent was distilled off in vacuo. 5.58 g (0.0198 mol) of the product were obtained in a purity of 99% (GC/MS) in a yield of 40%. The mother liquor of the reaction solution was freed completely from the solvent and the residue was recrystallized from hot heptane. 2.00 g (0.0068 mol) of the product were additionally obtained in a purity of 100% (GC/MS). The total yield was 54%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[CH:24]1([C:27]2[CH:28]=[C:29](F)[C:30]([N+:34]([O-:36])=[O:35])=[C:31]([F:33])[CH:32]=2)[CH2:26][CH2:25]1>CN(C)C=O>[CH:24]1([C:27]2[CH:32]=[C:31]([F:33])[C:30]([N+:34]([O-:36])=[O:35])=[C:29]([NH:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[CH:28]=2)[CH2:26][CH2:25]1
Reactant: O=[N+]([O-])c1c(F)cc(C2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C3CC3)cc(F)c2[N+](=O)[O-])CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 1.51 mmol, 302 mg) in dry dimethylformamide (10 ml), diisopropylethylamine (1 eq., 1.51 mmol, 0.26 ml) and 5-cyclopropyl-1,3-difluoro-2-nitrobenzene (D25, 1 eq., 1.51 mmol, 300 mg) were added at room temperature and the mixture was stirred under argon at 120° C. overnight. The crude mixture was then cooled to room temperature and poured onto water (10 ml). The aqueous solution was extracted with ethyl acetate (3×100 ml) and the organics were combined and washed with water and brine alternately (5×100 ml), dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound which was purified by chromatography (30% ethyl acetate-n-hexane 60%) to yield the title compound; 300 g, 0.79 mmol, 52%, M−−H=378.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:17])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH3:16])[CH2:10]1.ClC1C=C(C=CC=1)C(O)=[O:23]>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:17])[CH2:13][CH2:12][N+:11]([O-:23])([CH2:14][CH2:15][CH3:16])[CH2:10]1
Reactant: CCCN1CCC(O)(c2cccc(F)c2F)C1
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC[N+]1([O-])CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 68: (−)-3-(2,3-difluorophenyl)-1-propylpyrrolidin-3-ol (1.3 g, 5.4 mmol), dichloromethane (60 ml), m-chlorobenzoic acid (2.7 g, 16.2 mmol). Yield: 1.15 g. 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.06 (t, J=7.41 Hz, 3H) 1.96-2.16 (m, 2H) 2.69-2.83 (m, 1H) 2.84-3.00 (m, 1H) 3.35 (dt, J=10.92, 5.46 Hz, 2H) 3.50 (br. s., 2H) 3.67 (d, J=9.75 Hz, 1H) 3.77 (d, J=10.92 Hz, 1H) 3.89-3.99 (m, 1H) 7.18 (d, J=1.56 Hz, 1H) 7.13-7.20 (m, 1H) 7.62 (td, J=6.63, 5.46 Hz, 1H)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[N:18][C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]2[OH:28].Cl>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[N:18][C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]2[OH:28])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2ccc(NC(=O)OCc3ccccc3)cc2c1O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Benzyl chloroformate (7.5 g.) was added to a stirred solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (4.66 g.) in pyridine (75 ml.). The solution was stirred for 18 hours at room temperature and for 2 hours at 100° C. The solution was cooled and was poured onto a mixture of ice (500 g.) and 5N-hydrochloric acid (200 ml.). The pale solid which was precipitated was filtered off, washed with water, and recrystallised from a mixture of ethanol and water to give ethyl 6-benzyloxycarbonylamino-4-hydroxycinnolin-3-yl carboxylate, m.p. 250°-252° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][N:16]=1.[OH-].[Na+]>O>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][N:16]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: COc1ccnc(CCl)c1C
Reactant: Fc1ccc2nc(S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccnc(CSc2nc3ccc(F)cc3[nH]2)c1C

Procedure:
10.6 g of 5-fluoro-2-benzimidazolethiol were suspended in 570 ml of alcohol and treated with 13.1 g of 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride. A solution of 5 g of sodium hydroxide in 130 ml of water was added dropwise thereto while cooling with ice, the mixture was left to boil at reflux overnight and then concentrated to about 1/3 of the volume in a vacuum. After the addition of 500 ml of water the resulting crystals were filtered off and washed thoroughly firstly with water and then with ether. There was obtained 5-fluoro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]benzimidazole of melting point 128°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16].CC(C)([O-])C.[K+]>CN(C=O)C>[F:13][C:14]([F:18])([F:17])[CH2:15][O:16][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1
Reactant: OC1(c2cnccc2Cl)CCC1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1(c2cnccc2OCC(F)(F)F)CCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
To a solution of 1-(4-chloropyridin-3-yl)cyclobutanol (Example 108a, 0.83 g, 4.52 mmol) in dry DMF (20 ml) under an argon atmosphere was added 2,2,2-trifluoroethanol (CAN 75-89-8, 904 mg, 653 μl, 9.04 mmol) and potassium tert-butoxide (533 mg, 4.75 mmol). The reaction mixture was stirred at room temperature for 20 minutes and stirred at 90° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/(solution 3% Et3N in ethylacetate) to yield the title compound (885 mg, 71%) as a yellow oil. MS (ESI, m/z): 248.5 (M+H+).