Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C@H:11]([OH:12])[CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].N1C=CC=CC=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[S:33]([O:12][CH:11]1[CH2:13][N:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH2:10]1)([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CC(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of Boc-Hyp-OtBu (0.5 g, 1.74 mmol) in DCM (20 mL) were added pyridine (0.550 g, 6.96 mmol) and p-toluenesulfonyl chloride (0.663 g, 3.48 mmol) at r.t. After being stirred at r.t. for 24 h, the reaction mixture was quenched with 1M HCl and extracted with DCM. The organic layer was successively washed with 1M HCl, water, brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel and provided pure product, Cpd C (yellow solid). Spectral Data: 1H-NMR (CDCl3/400 MHz): 7.82 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 5.05 (m, 1H), 4.28 (m, 1H), 3.59 (m, 2H), 2.49 (s, 3H), 2.57 (m, 1H), 2.13 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H). MS (ES+, m/z): 442.2 (M++1, 30.0).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[C:34]#[N:35]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:30]2[CH:31]=[CH:32][C:33]([C:34]#[N:35])=[C:28]([F:27])[CH:29]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: N#Cc1ccc(B(O)O)cc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(C#N)c(F)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-fluoro-4-cyano-phenylboronic acid, 5-(4-cyano-3-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a cream-colored solid (yield=65%).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.C[O:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O)=O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:6]1[CH:5]=[CH:4][N:3]=[C:2]2[C:7]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11](=[O:10])[NH:1]2
Reactant: COC(=O)c1ccccc1B(O)O
Reactant: Nc1ncccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c2ncccc2c2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
2-Amino-3-bromopyridine (173 mg, 1.00 mmol), 2-methoxycarbonyl-phenylboronic acid (225 mg, 1.25 mmol), Pd(OAc)2 (9 mg, 0.04 mmol), S-Phos (33 mg, 0.08 mmol), and K2CO3 (414 mg, 3.00 mmol) were dissolved in dioxane/H2O (2.0 mL, 10/1, v/v), and stirred overnight at 100° C. The reaction mixture was concentrated, suspended in EtOAc/H2O, and filtered. The precipitate was washed with EtOAc/H2O, and dried under vacuum to provide 1 (75 mg, 38% yield) as a solid. LC-MS (M+H=197, obsd.=197). 1H NMR (400 MHz, d6-DMSO): δ 12.08 (s, 1H), 8.83 (d, 1H), 8.55 (d, 1H), 8.49 (dd, 1H), 8.42 (d, 1H), 7.90 (t, 1H), 7.70 (t, 1H), 7.33 (dd, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:58]=[CH:57][C:7]([CH2:8][O:9][C:10]([CH2:12][O:13]/[N:14]=[C:15](/[C:32]2[N:33]=[C:34]([NH:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:35][CH:36]=2)\[C:16]([O:18]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(O)=O>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:15](=[N:14]/[O:13][CH2:12][C:10]([O:9][CH2:8][C:7]2[CH:57]=[CH:58][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])/[C:16]([OH:18])=[O:17])[N:33]=1
Reactant: O=C(CO/N=C(\C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OCc1ccc([N+](=O)[O-])cc1
Solvent: O=CO
Product: Nc1nc(/C(=N/OCC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)O)cs1

Procedure:
Diphenylmethyl (Z)-2-(4-nitrobenzyloxycarbonyl)methoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (2.5 g) was treated with formic acid under the conditions described in Example 23d, increasing the reaction time to 26 h. The title compound was obtained as a white solid (1.13 g); νmax (Nujol) 3520, 1745, 1605, and 1510 cm-1 ; δH ((CD3)2SO) inter alia 4.85 (2H, s), 5.37 (2H, s), 6.86 (1H, s), 7.23 (2H, br. s), 7.57 and 8.23 (4H, ABq, J 8 Hz).
Reaction SMILES: OC1C=CC=C2C=1C(C#N)=CN2.[O:13]1[CH2:28][CH:14]1[CH2:15][O:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([C:26]#[N:27])=[CH:20][NH:21]2.[CH2:29]([O:32][C:33]1[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=1[O:35][CH2:36][CH2:37][NH2:38])[CH:30]=[CH2:31]>>[OH:13][CH:14]([CH2:28][NH:38][CH2:37][CH2:36][O:35][C:34]1[CH:39]=[CH:40][CH:41]=[CH:42][C:33]=1[O:32][CH2:29][CH:30]=[CH2:31])[CH2:15][O:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([C:26]#[N:27])=[CH:20][NH:21]2
Reactant: N#Cc1c[nH]c2cccc(OCC3CO3)c12
Reactant: C=CCOc1ccccc1OCCN
Agent: N#Cc1c[nH]c2cccc(O)c12
Product: C=CCOc1ccccc1OCCNCC(O)COc1cccc2[nH]cc(C#N)c12

Procedure:
Compounds of general formula (I) can be further reacted by known methods, for example by saponification and decarboxylation to give 4-hydroxyindole or 4-hydroxy-6-methylindole, or by aminolysis and dehydration to give 4-hydroxy-3-cyanoindole or 4-hydroxy-3-cyano-6-methylindole, which, by reaction with epichlorohydrin and alkylamino derivatives, give aminopropanols with useful pharmacological properties (see Federal Republic of Germany Patent Specification Nos. 25 08 251; 27 37 630; 29 05 877 and 30 30 047). However, compounds of general formula (I) can also be reacted to give aminopropanol derivatives directly, whereafter the compounds obtained are subsequently changed. Thus, for example, from 4-hydroxy-3-cyanoindole (see Federal Republic of Germany Patent Specification No. 30 29 980) there is obtained 4-(2,3-epoxypropoxy)-3-cyanoindole which is reacted with 2-(2-allyloxyphenoxy)-ethylamine to give the pharmacologically effective 4-{2-hydroxy-3-[2-(2-allyloxyphenoxy)-ethylamino]-propoxy}-3-cyanoindole (see Example 3h) of Federal Republic of Germany Patent Specification No. 30 30 047).
Reaction SMILES: [NH2:1][C@H:2](/[C:29](/[CH3:37])=[CH:30]/[C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1)[CH2:3][C@@H:4]1[O:28][C@:5]1([CH3:27])[CH2:6][CH2:7][C:8](=[O:26])[C@H:9]([CH3:25])[C@H:10]([OH:24])[C@@H:11]([CH3:23])[C:12](=[O:22])[C:13]([CH3:21])([CH3:20])[C@@H:14]([OH:19])[CH2:15][C:16]([OH:18])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C.CN(C)C=O.O>[O:28]1[C@@H:4]2[C@@:5]1([CH3:27])[CH:6]=[CH:7][C:8](=[O:26])[C@H:9]([CH3:25])[C@H:10]([OH:24])[C@@H:11]([CH3:23])[C:12](=[O:22])[C:13]([CH3:21])([CH3:20])[C@@H:14]([OH:19])[CH2:15][C:16](=[O:18])[NH:1][C@H:2]([C:29]([CH3:37])=[CH:30][C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1)[CH2:3]2
Reactant: C/C(=C\c1csc(C)n1)[C@@H](N)C[C@@H]1O[C@]1(C)CCC(=O)[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CC(=Cc1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)C=CC(=O)[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of (3S,6R,7S,8R,12R,13S,15S,16E)-15-amino-3,7-dihydroxy-5,9-dioxo-12,13-epoxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-16-heptadecenoic acid (540 mg) in acetonitrile/dimethylformamide (20:1 v/v, 150 mL) is cooled to 0° C. and treated sequentially with 1-hydroxybenzotriazole (0.135 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.5 g). The mixture is warmed to ambient temperature and kept for 12 hours, then diluted with water and extracted with ethyl acetate. The extract is washed sequentially with water, sat. NaHCO3, and brine, then dried over Na2SO4, filtered, and evaporated. The product is purified by flash chromatography on SiO2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[CH3:23])=[S:12].[CH3:24][NH:25][C:26](=S)[SH-:27]C>>[CH3:23][C:22]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:17][S:16][CH2:15][CH2:14][NH:13][C:11](=[S:12])[NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][CH3:24])=[S:27]
Reactant: CNC(=S)[SH-]C
Reactant: Cc1[nH]cnc1CSCCNC(=S)NCCCCCCCCN
Product: CNC(=S)NCCCCCCCCNC(=S)NCCSCc1nc[nH]c1C

Procedure:
Reaction of N-(8-aminooctyl)-N'-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]thiourea (see Example 22) with N,S-dimethyldithiocarbamate yields 1-[N'-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)thioureido]-8-[N'-methylthioureido]octane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:10]=1[O:11][C:12]1[CH:13]=[C:14](Cl)[CH:15]=[CH:16][C:17]=1[C:18]2=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C)[CH:29]=[O:30]>O>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:10]=1[O:11][C:12]1[CH:13]=[C:14]([O:30][CH3:29])[CH:15]=[CH:16][C:17]=1[C:18]2=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Cl)cc2oc2c(OCc3ccccc3)cccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(=O)c3cccc(OCc4ccccc4)c3oc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-benzyloxy-3-chloroxanthone (8.5 g.), sodium hydride (3 g.), methaol (20 ml.) and dimethylformamide (100 ml.) is stirred at room temperature for 24 hours. The mixture is poured into water and the precipitate is filtered. The residue is recrystallised from isopropanol to give 5-benzyloxy-3-methoxyxanthone, m.p. 158° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:15]2[CH2:20][C:19](=O)[CH2:18][CH2:17][N:16]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:11]=[CH:12][C:13]=1[F:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[F:7][C:8]1[CH:9]=[C:10]([CH:15]2[CH2:20][C:19](=[CH2:1])[CH2:18][CH2:17][N:16]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)C1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Potassium tert-butoxide (0.81 g, 7.2 mmol) was added to a suspension of methyltriphenylphosphonium bromide (2.58 g, 7.2 mmol) in tetrahydrofuran (20 mL) and the resulting mixture was stirred at room temperature for one hour. A solution of phenylmethyl 2-(3,4-difluorophenyl)-4-oxopiperidine-1-carboxylate (1.00 g, 2.9 mmol) (reagent preparation 20) in tetrahydrofuran (5 mL) was added and the resulting mixture was stirred at 35° C. for two hours. The mixture was cooled, diluted with hexane (100 mL), filtered, and the filtrate washed with water then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20% ethyl acetate in hexanes) to give phenylmethyl 2-(3,4-difluorophenyl)-4-methylidenepiperidine-1-carboxylate (0.79 g, 79% yield), MS (EI) for C20H19F2NO2: 344 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][O:23][CH2:24][C:25]3([C:28]#[N:29])[CH2:27][CH2:26]3)[C:11](=[O:32])[C@@H:10]([CH2:33][C:34]([OH:36])=[O:35])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:42]>CC(O)(C)C>[C:28]([C:25]1([CH2:24][O:23][CH2:22][C@@H:21]([N:12]2[C@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:9][C@H:10]([CH2:33][C:34]([OH:36])=[O:35])[C:11]2=[O:32])[CH2:30][CH3:31])[CH2:27][CH2:26]1)(=[O:42])[NH2:29]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC[C@@H](COCC1(C#N)CC1)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC[C@@H](COCC1(C(N)=O)CC1)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of 10 mg (0.02 mmol) 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((1-cyanocyclopropyl)methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 11) and potassium hydroxide (3.2 mg, 0.06 mmol) in t-BuOH (189 μL) was stirred at 85° C. for 24 h. The reaction was acidified (10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 35 to 75% acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) provided the title compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])[CH:6]=[CH:7][CH:8]=1.C(#N)C.[Br-].[Li+].CCN(CC)CC>CC(OC)(C)C.O>[CH3:22][O:21][C:19]([N:10]1[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:4]=1)=[O:20]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2cccc(C(F)(F)F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1c1cccc(C(F)(F)F)c1
Yield: 90.8 %

Procedure:
Dimethyl 2-(3-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (1.7 g, 4.92 mmol) was dissolved into acetonitrile (22 mL) and water (0.440 mL), then lithium bromide (3.42 g, 39.38 mmol) was added. Et3N (2.74 mL, 19.69 mmol) was added and the resulting yellow suspension was heated under reflux for 2 h. Water (50 mL) and MTBE (150 mL) were added. The phases were separated and the organic layer was extracted with water (2 times). The pooled water layers were acidified to pH 1 with 3.8 M HCl and extracted with MTBE (2 times). The combined organic layer was dried over Na2SO4, filtered and evaporated yielding 1-(methoxycarbonyl)-2-(3-(trifluoromethyl)phenyl)piperidine-4-carboxylic acid (1.48 g, 91%) as a slightly yellow semi-solid. MS m/z 332 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:43])[C:11]([C:41]#[N:42])=[C:12]([NH:24][C@H:25]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:32][C:33](=[O:39])[N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[C:26]2=[O:40])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([CH3:22])=[CH:19][C:18]=3[CH:23]=2)=[CH:6][CH:5]=1.C1COCC1>O>[C:41]([C:11](=[C:12]([NH:24][C@H:25]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:32][C:33](=[O:39])[N:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)[C:26]1=[O:40])[NH:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH3:22])=[CH:19][C:18]=2[CH:23]=1)[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:44])=[O:2])=[CH:5][CH:6]=1)=[O:43])#[N:42]
Reactant: COC(=O)c1ccc(C(=O)C(C#N)=C(Nc2ccc3oc(C)cc3c2)N[C@H]2CCCCN(CC(=O)N3CCCC3)C2=O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2cc(NC(N[C@H]3CCCCN(CC(=O)N4CCCC4)C3=O)=C(C#N)C(=O)c3ccc(C(=O)O)cc3)ccc2o1
Reaction time: 24 h
Yield: 83.4 %

Procedure:
The compound of Example 1 (0.442g, 0.740 mmol) was dissolved in 10 mL of 1:1 water:THF and the mixture was cooled to 0° C. To the solution was added LiOH monohydrate (0.31 g, 7.4 mmol). The reaction mixture was allowed to come to room temperature. After stirring for 24 h, the reaction mixture was concentrated by in vacuo and the residue was dissolved in methylene chloride. The mixture was extracted 2×25 mL with water. The combined aqueous layers were neutralized with 1 N HCl to pH 4 and were extracted 2×25 mL with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated to give the title compound (360 mg, 83%) as yellow solid: MS (ESI, pos. ion) m/z 584 (M+H); HPLC (method B) tR=3.8 min, purity: >96%.
Reaction SMILES: C(O)C.C(=S)(OCC)[S:5][C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1.[OH-].[Na+]>O>[F:15][C:12]([F:13])([F:14])[C:9]1[N:8]=[CH:7][C:6]([SH:5])=[CH:11][CH:10]=1
Reactant: CCOC(=S)Sc1ccc(C(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1ccc(S)cn1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To an ethanol (2 ml) solution of O-ethyl S-(6-trifluoromethylpyridin-3-yl) dithiocarbonate (160 mg, 0.60 mmol) was added a 1N aqueous sodium hydroxide solution (2 ml). The resulting mixture was stirred at 65° C. for 2 hours. After the reaction mixture was cooled to room temperature and then, water was added thereto. The resulting mixture was washed with dichloromethane. The water layer was acidified with 1N hydrochloric acid, and the product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to afford 6-trifluoromethylpyridine-3-thiol as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[C:12]1([O:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl.CCOCC>[F:10][C:8]([F:9])([F:11])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:19](=[O:20])[O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)ccn1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccn1)Oc1ccccc1
Yield: 92.2 %

Procedure:
A solution of the commerically available 2-amino-4-trifluoromethylpyridine (20.86 g, 128.7 mmol) in 250 mL CH2Cl2 was treated with phenylchloroformate (17.81 mL, 141.5 mmol) and pyridine (22.85 mL, 283 mmol). During addition of the pyridine a yellow precipitate formed and a considerable exotherm was observed. After 0.5 h the homogeneous reaction was diluted with 1 L Et2O and washed with 1N bisulfate buffer (pH 2) and sat. NaHCO3. The organic layer was dried with Na2SO4 and evaporated to yield a gray solid. Tritruration with Et2O:hexanes (1:5) gave the title compound as cottony white crystals (33.5 g, 92% Yield). 1H-NMR (DMSO-d6) 11.28 (s, 1H), 8.60 (d, J=5.1 Hz, 1H), 8.12 (bs, 1H), 7.40 to 7.48 (m, 3H), 7.22 to 7.31 (m, 3H); MS [M+H]+=283.1; LCMS RT=3.51.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:36][C:37](Cl)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.24) (135 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (43 mg, 15%). MS (ISN) 587.3 [(M−H)−]; mp 272° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][NH:24][CH3:25]>C(O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:25])[CH3:23])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CNC
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Solvent: CCO
Product: CN(C)CCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and N,N-dimethylamine in ethanol were converted to yield [4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl]-dimethyl-amine as light yellow semisolid, MS: 404 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([CH:13]=1)[O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[N+:17]([O-])([OH:19])=[O:18].C(OCC)(=O)C.O>S(=O)(=O)(O)O>[N+:14]([C:5]1[CH:4]=[C:3]([N+:17]([O-:19])=[O:18])[C:2]([F:1])=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 14.5 g (63 mmol) methyl 5-fluoro-2-nitrophenoxyacetate in 17 ml conc. sulfuric acid (H2SO4) at 8° C. was added slowly via an addition funnel a mixture of 5.0 ml (76 mmol) of 70% nitric acid and 5.0 ml of conc. H2SO4. After addition was complete, the reaction was stirred an additional 1 hour at 15° C. The reaction mixture was poured into 150 ml of 1:1 ethyl acetate/water and the resulting layers were separated. The aqueous phase was extracted with ethyl acetate (2×60 ml) and the combined organics were dried (Na2SO4) and concentrated in vacuo to give 17.2 g (98% yield) of the desired nitrated product as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:9][CH:10]=3)[C:5]([CH3:30])([CH3:29])[C:4]=2[CH:3]=1.[C:31]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>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>[C:31]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:9][CH:10]=3)[C:5]([CH3:30])([CH3:29])[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: COc1ccc(-c2ccc3c(c2)C(C)(C)c2cc(Br)ccc2-3)c(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)C(C)(C)c2cc(-c4ccccc4-c4ccccc4)ccc2-3)c(-c2ccccc2)c1
Temperature: 110 °C
Yield: 68 %

Procedure:
A mixture of 3.4 g (7.5 mmol) of 2-bromo-7-(5-methoxybiphenyl-2-yl)-9,9-dimethyl-9H-fluorene, 2 g (10 mmol) of biphenyl-2-ylboronic acid, 0.12 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of 2M Na2CO3, 20 ml of EtOH and 60 ml toluene was degassed and placed under nitrogen, and then heated at 110° C. for 8 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (2.7 g, 5.1 mmol, 68%).