Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]([O-])=[O:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>>[NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:26]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[NH:17][CH:18]=[CH:19]4)=[O:27])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc2[nH]ccc2c1
Product: Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc4[nH]ccc4c3)cc2)cc1

Procedure:
Compound 346 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 1H-indole-5-carboxylate. [M+H]+ calcd for C22H17N3O2: 356.14; found: 355.90.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:29])C=1>CO>[CH3:1][N+:2]1([O-:29])[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1CCC(Oc2ccccc2)(c2ccccc2)CC1
Solvent: CO
Product: C[N+]1([O-])CCC(Oc2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.5 g of 1-methyl-4-phenoxy-4-phenylpiperidine are dissolved in 4 ml of methanol, and 1.7 g of 80% strength m-chloroperbenzoic acid, dissolved in methanol, are added slowly thereto while cooling with ice. After stirring the mixture at room temperature for 3 hours, the solvent is stripped off and the residue is partitioned between concentrated sodium hydroxide solution and chloroform. The crude N-oxide hydrate (which remains after drying the chloroform phase and evaporating off the solvent) is taken up in a little methanol, and the equivalent amount of methanolic fumaric acid is added. 1 g of a colorless precipitate is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[K+].[S:16]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-])=O)=[CH:22][CH:21]=1)([OH:19])(=[O:18])=[O:17].C(N=C=NCCCN(C)C)C.Cl>O>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:24]([C:23]3[CH:22]=[CH:21][C:20]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:28][CH:27]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C([O-])c1ccc(S(=O)(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Reaction time: 18 h
Yield: 67.6 %

Procedure:
A mixture of 5,6-diamino-1,3-diethyl-2,4(1H,3H)-pyrimidinedione (41.2 g, 0.208 moles), 4-sulfobenzoic acid monopotassium salt (50.0 g, 0.208 moles), and water (250 ml) is prepared, and the pH adjusted to 6.0. Ethyl-3-(3-dimethylaminopropyl)carbodiimide (39.9 g, 0.208 moles) is added in one portion, and the pH of the resulting solution maintained at 5.5±0.5 with the dropwise addition of 4 N hydrochloric acid. When the pH of the solution ceases to rise, the mixture is concentrated on a rotary evaporator, and the residue taken up in 400 ml 10% potassium hydroxide and stirred for 18 hours. At the end of this time, the solution is boiled under reflux for one hour, cooled, filtered, and made acidic with the portionwise addition of 12 N hydrochloric acid. The resulting suspension is cooled and filtered; the solids are triturated with ethanol, filtered, and dried to yield 51.2 grams of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)-benzenesulfonic acid; mp greater than 360° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[C:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[N:29]([CH2:36][C:37]([OH:39])=O)[N:28]=1.CCN(C(C)C)C(C)C.[CH3:51][C:52]1[N:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=2C)[C:54]([CH:57]([NH2:65])[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[N:55][N:56]=1>CN(C=O)C>[CH3:51][C:52]1[N:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[C:54]([CH:57]([NH:65][C:37](=[O:39])[CH2:36][N:29]2[C:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[C:27]([C:26]([F:25])([F:41])[F:40])=[N:28]2)[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[N:55][N:56]=1
Reactant: Cc1ccccc1-n1c(C)nnc1C(N)Cc1ccccc1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnc(C(Cc2ccccc2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1-c1ccccc1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 10F (29.2 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 9.16-8.86 (m, 1H), 7.39 (dd, J=16.8, 8.4 Hz, 2H), 7.28 (d, J=7.2 Hz, 1H), 7.16 (t, J=6.3 Hz, 3H), 6.90 (td, J=51.4, 7.6 Hz, 3H), 4.74-4.51 (m, 3H), 3.10 (s, 1H), 2.94 (dd, J=13.5, 8.9 Hz, 1H), 2.44-2.10 (m, 4H), 2.03 (d, J=4.7 Hz, 3H), 1.59 (s, 4H). MS (m/z) 509 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]#N)=[CH:7][C:6]([CH2:11][CH3:12])=[C:5]([CH3:13])[N:4]=1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:27]CC1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:13])[C:6]([CH2:11][CH3:12])=[CH:7][C:8]=1[CH:9]=[O:27]
Reactant: C1CCOC1
Reactant: CCc1cc(C#N)c(OC)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: CCc1cc(C=O)c(OC)nc1C
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a solution of 2-methoxy-3-cyano-5-ethyl-6-methylpyridine (1.0 g, 5.68 mmol) in dry tetrahydrofuran (50 mL) under a nitrogen atmosphere and cooled to -70° C., was added 1.3M diisobutyl aluminum hydride/THF (17.4 mL, 22.7 mmol). The resulting mixture was allowed to warm to room temperature and stir for 15-20 hours. The reaction mixture was acidified with 1N hydrochloric acid and then neutralized with aqueous sodium bicarbonate. Water was then added and the product extracted into diethyl ether. The etheral extract was dried (Na2SO4), filtered and the solvent evaporated. This residue was flash chromatographed on silica gel eluting with 10% diethyl ether/pentane to give the product.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].C([O:8][C:9]([C:11]1[S:15][C:14]2[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:13]=2[CH:12]=1)=O)C>C(O)C>[OH:3][NH:2][C:9]([C:11]1[S:15][C:14]2[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:13]=2[CH:12]=1)=[O:8]
Reactant: CCOC(=O)c1cc2cc(OC)c(OC)cc2s1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2cc(C(=O)NO)sc2cc1OC
Reaction time: 72 h
Yield: 87.3 %

Procedure:
Hydroxylamine hydrochloride (5.3 g) was dissolved in warm ethanol (100 ml). The solution was stirred under an atmosphere of nitrogen and treated with a warm solution of potassium hydroxide (6.4 g) in ethanol (50 ml). After 10 min. a solution of 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid ethyl ester (10 g) in ethanol (250 ml) was added and the resultant mixture was allowed to stand at room temperature for 72 hours. The resultant suspension was filtered to remove the precipitated potassium chloride and the filtrate was evaporated to dryness. The resultant yellow residue was dissolved in water (250 ml), filtered and the filtrate was acidified with 5M hydrochloric acid. The precipitated product was filtered and dried at 65° C. under vacuum to give N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboxamide (8.3 g). A portion crystallised from acetone had a melting point: 179°-180° C.
Reaction SMILES: O1CCC[CH2:2]1.[OH:6][CH2:7][CH:8]([CH3:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CI.CO>CCOCC>[CH3:2][O:6][CH2:7][CH:8]([CH3:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: CC(CO)Cc1ccccc1
Solvent: CO
Solvent: CI
Solvent: CCOCC
Product: COCC(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
220 ml (1.9 mole) of KH (35% in oil) were placed, under a N2 -atmosphere, into a 4.5 l reactor and washed 4 times with pentane, in order to remove all traces of oil. 1.5 l of dry tetrahydrofurane were added before the dropwise addition of a solution of 259 g (1.73 mole) of 1-hydroxy-2-methyl-3-phenylpropane and 500 ml of dry tetrahydrofurane. The reaction was stirred for 15 hours at room temperature. Then 285 g (2.01 mole) of methyl iodide were added dropwise over a period of 2 hours, and stirring was continued at room temperature for another 2 hours. A possible excess of KH was hydrolyzed by adding 50 ml of methanol, then the reaction mixture was poured on ice. The product was taken up in ether, which was washed 3 times with a saturated NH4Cl solution and then with brine to neutrality. After drying over Na2SO4, the solution was filtered, concentrated and then distilled over a Vigreux-type column (boiling point: 100° C. at 5×102Pa).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][C:3]=1I.C([O:31][B:32](OC(C)C)[O:33]C(C)C)(C)C>C1COCC1.C([Li])CCC>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][C:3]=1[B:32]([OH:33])[OH:31]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1c(I)ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c1F
Reaction time: 2 h

Procedure:
To a solution 2,3-difluoro-1-iodo-4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-benzene (10A) (1 equi.) in THF (5 mL/mmole), butyllithium (1.3 equi.) was added at −78 C. The reaction mixture was stirred at that temperature for 2 hr,. Then triisopropylborate (1 equi.) was added at that temperature. The reaction mixture was stirred at that temperature for 1 h and at room temperature for 10 h, quenched with water, extracted with ethyl acetate washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by recrystallization from hexane afforded 2,3-difluoro-4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-phenylboronic acid (11A), as a white solid (75%).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1>C(Cl)Cl>[NH2:3][C:4]1[C:9]([Br:1])=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: Cc1ccc(N)nc1
Solvent: ClCCl
Product: Cc1cnc(N)c(Br)c1
Reaction time: 2 h

Procedure:
Bromine (3.19 g) was added dropwise at 0° C. to a solution of 2-amino-5-picoline in 75 mL CH2Cl2. After about two hours at room temperature, the reaction was extracted with saturated sodium carbonate solution, then sodium thiosulfate solution. The combined aqueous extracts were washed with CH2Cl2, and the combined organic extracts washed with saturated NaCl, dried (Na2SO4) and concentrated giving 3.59 g crude material. The product was purified by flash chromatography on silica gel, eluting with petroleum ether with increasing amounts of CH2Cl2 (0-40%), giving 3.05 g 2-amino-3-bromo-5-picoline, m.p. 68°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl.Cl[CH2:12][CH2:13][NH2:14].C([O-])([O-])=O.[K+].[K+].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:12][CH2:13][NH2:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(SCCN)cc1
Yield: 97 %

Procedure:
4-Methoxythiophenol (50 g, 0.357 mol), 2-chloroethylamine monohydrochloride (39.8 g, 0.343 mol.), K2CO3 (78.8 g, 0.57 mol) and diisopropyl ethylamine (32 mL, 0.178 mol) were mixed in 200 mL of THF. The mixture was degassed for 5 min. under reduced pressure and refluxed under argon overnight. The solvent was removed and water (300 mL) was added to the flask. The mixture was extracted with dichloromethane (3×200 mL). The organics were collected, dichloromethane was removed and 50 mL conc. HCl was added, followed by 200 mL of water. The solution was extracted with 1:1 EtOAc/hexane (3×200 mL). The aqueous layer was adjusted to pH 10 with 2 M NaOH, and was extracted with dichloromethane (3×200 mL). The combined organic solution was dried over anhydrous sodium sulfate. Removal of solvent provided 61 g of the target compound as a colorless liquid, with a yield of 97%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:24])=[N:17][C:18]([N:21]([CH3:23])[CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([OH:28])[CH2:26][CH3:27])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P)CCC.[F:52][C:53]([F:57])([F:56])[CH2:54]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[N:17][C:16]=4[CH3:24])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([O:28][CH2:54][C:53]([F:57])([F:56])[F:52])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Agent: CCCCP
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
A mixture of 1-{9-chloro-1-[6-(dimethylamino)-2-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}propan-1-ol (71.1 mg, 0.178 mmol), 1,1′-(azodicarbonyl)dipiperidine (89.7 mg, 0.355 mmol) and n-butylphosphine (71.8 mg, 0.355 mmol) in tetrahydrofuran (2.0 mL) was stirred at room temperature for 15 min. 2,2,2-Trifluoroethanol (178 mg, 1.78 mmol) was added to the mixture, and the mixture was stirred at 60° C. for 7 hr. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 35-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (30.8 mg, 0.0639 mmol, 36%)
Reaction SMILES: [NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:24]([NH:26][C@H:27]([C:37]([NH:39][C@H:40]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:38])[CH2:28][CH2:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:25])[CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:54]([O:57][CH2:58][CH3:59])(=[O:56])C>>[NH:1]([C:54]([O:57][CH2:58][C:59]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:37]=1)=[O:56])[C@H:2]([C:12]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:24]([NH:26][C@H:27]([C:37]([NH:39][C@H:40]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:41][O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:38])[CH2:28][CH2:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:25])[CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH3:3]
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 80.7 %

Procedure:
6.62 g. (8.7 mmoles) of H-28-31-OtBu are dissolved in 65 ml. of ethyl acetate, and 2.72 g. (8.5 mmoles) of Z-Ala-ONSu are added to the solution. After 5 minutes of stirring, a homogeneous solution is formed. The reaction mixture is stirred for one hour; at that time the product separates from the mixture. The mixture is left to stand overnight, thereafter the product is filtered off and washed with ethyl acetate. The crude product is recrystallized from 65 ml. of ethyl acetate. 6.61 g. (80.7 %) of Z-27-31-OtBu are obtained. M.p.: 193°-195° C, Rf11 = 0.75.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:21][C:17]1[N:16]=[C:15]([C:6]2[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Fc1cccc(Br)n1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2cccc(F)n2)c(OC)n1
Yield: 57.6 %

Procedure:
2,4-Dimethoxy-pyrimidine-5-boronic acid (966 mg, 5.3 mmol) was dissolved in degassed n-PrOH (60 ml) and then 2-bromo-6-fluoropyridine (850 mg, 4.8 mmol), Na2CO3 (1.676 g, 15.8 mmol), PPh3 (400 mg, 1.52 mmol) and Pd(OAc)2 (116 mg) were added. The suspension was stirred at reflux for 3 hours. The solvent was evaporated under vacuum and the crude was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The crude was triturated with iPrOH to give 650 mg of the title compound as a white powder (52% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH2:3]1.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH:34](OS(C)(=O)=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OC(=O)C)C>[CH2:14]([O:21][C:22]([N:24]1[CH2:25][CH2:26][CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([NH:1][C@@H:2]2[C:8](=[O:9])[NH:7][C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[S:4][CH2:3]2)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH2:29]1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@H]1CSc2ccccc2NC1=O
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2NC1=O
Yield: 44.2 %

Procedure:
A mixture of 3(R)-amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.7 g) and ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (5.4 g) is heated at 100°-130° C. for 3 hours. After cooling, the mixture is dissolved in ethylacetate (200 ml) and the solution is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (2.9 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:7]2[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:19][CH2:18]1
Reactant: COCCN1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 80 °C
Yield: 105.1 %

Procedure:
To 4-fluoro-2-(methyloxy)-1-nitrobenzene (which may be prepared according to Example 22, step A) (1 g, 5.8 mmol) in 15 mL of DMSO was added, 1-[2-(methyloxy)ethyl]piperazine (0.92 g, 6.4 mmol), and K2CO3 (2.4 g, 17.4 mmol). The mixture was heated to 80° C. overnight. The mixture was then poured into 100 mL of H2O and extracted with EtOAc, washed with a saturated NaCl solution, dried over Na2SO4, filtered and rotovapped to dryness to give 1.8 g of crude 1-[2-(methyloxy)ethyl]-4-[3-(methyloxy)-4-nitrophenyl]piperazine. MS (ESI): 296 [M+H]+. This material was dissolved in 15 mL EtOH and 1 mL DMF in a 100 mL round bottom flask. Platinum on Carbon (5% by weight) (0.2 g) was added and the flask was flushed with N2. After about 15 min, a balloon containing H2 was added and the N2 was removed. H2 was bubbled through the solution for a few minutes. The reaction mixture was let stir overnight under balloon pressure. In the morning the balloon was removed and the flask flushed with N2 to remove all H2. The solution was filtered through celite and evaporated to afford the title compound of step A (1.49 g, 5.62 mmol, 92%); MS (ESI): 266 [M+H]+.
Reaction SMILES: Br[C:2]1[S:11][C:5]2[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.O.COCCOC>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:11][C:5]3[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=c1[nH]ccc2cc(Br)sc12
Reactant: OB(O)c1ccc(Cl)cc1
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: CCO
Solvent: O
Solvent: COCCOC
Product: O=c1[nH]ccc2cc(-c3ccc(Cl)cc3)sc12
Temperature: 85 °C
Yield: 89.3 %

Procedure:
Combine 2-bromo-6H-thieno[2,3-c]pyridin-7-one (25.0 g, 108.7 mmol), 4-chlorophenylboronic acid (18.7 g, 119.5 mmol), sodium carbonate (23.5 g, 217.3 mmol), ethanol (121 mL), 1,2-dimethoxyethane (604 mL), and water (121 mL). Purge the mixture with nitrogen for 20 min. Add tetrakis(triphenylphosphine)palladium (3.77 g, 3.26 mmol). Heat the reaction mixture at 85° C. overnight. Allow the reaction to cool to RT. Reduce the reaction solvent volume to half on a rotory evaporator. Filter the mixture with water (2×400 mL), ether (400 mL), and ethylacetate (20 mL) and dry the solids in vacuo at 40° C. to give 25.4 g (89%) of the title compound. LC-MS/ES m/z (35Cl) 262.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([N+:14]([O-])=O)[C:5]([N+:17]([O-])=O)=[CH:4][C:3]1=2>CO.[Ni]>[CH3:12][C:9]1([CH3:13])[CH2:10][CH2:11][C:2]([CH3:1])([CH3:20])[C:3]2[CH:4]=[C:5]([NH2:17])[C:6]([NH2:14])=[CH:7][C:8]1=2
Reactant: CC1(C)CCC(C)(C)c2cc([N+](=O)[O-])c([N+](=O)[O-])cc21
Agent: [Ni]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(N)c(N)cc21
Reaction time: 48 h
Yield: 85.6 %

Procedure:
39.0 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2,3-dinitro-naphthalene in 1300 ml of methanol were hydrogenated with Raney-nickel in a 2 l hydrogenation flask. The H2 -uptake after 48 hours was 20.7 l (18.8 l=theory). The catalyst was removed by filtration under suction, the solution was again filtered and the filtrate was evaporated in vacuo. The residue was crystallized from isopropanol. There were obtained 26.2 g (85.5% of theory) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2,3-napthalene-diamine of melting point 188°-189° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1(O)[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1>FC(F)(F)C(O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH:10]=1
Reactant: CCCN1CCC(O)(c2cccc(F)c2F)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCCN1CC=C(c2cccc(F)c2F)CC1

Procedure:
Preparation according to preparation 4: 4-(2,3-difluorophenyl)-1-propylpiperidin-4-ol (6.43 g, 25.2 mmol), trifluoroacetic acid (40 ml). Yield: 3.35 g. MS m/z (rel. intensity, 70 eV) 237 (M+, 26), 209 (14), 208 (bp), 151 (20), 127 (23).