Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[CH3:6])[CH3:2].[NH:22]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:23]([C:25](O)=[O:26])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([N:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:25](=[O:26])[C@@H:23]([NH:22][C:28](=[O:29])[O:30][CH2:31][CH:32]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=2[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:24])[CH3:6])[CH3:2]
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2cccnc12
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
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
Solvent: O
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine (Compound IX-3) 13.0 g (45 mmol) and Fmoc-Ala-OH 18.3 g (58.8 mmol) were dissolved in DMF (200 ml). HATU (25.6 g, 67.5 mmol) and DIEA (8.7 g, 67.5 mmol) were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was poured into water (800 ml). The solution was extracted with EA (300 ml×3). The combined extracts were dried over Na2SO4 and then filtered. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=30:1 to 5:1 to give the title compound 18.1 g, (yield 69%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:4]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)c2ccccc2[nH]c1=O
Product: CCOC(=O)c1c(Cl)nc2ccccc2c1C

Procedure:
A suspension of ethyl 4-methyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate (obtained according to 3.a, 15.2 g, 0.066 mol) in phosphoryl chloride (243 ml) is taken to reflux for 6 hours. The phosphoryl chloride is evaporated under reduced pressure without taking to dryness, and the viscous residue is poured into ice cold water (300 ml). The precipitate obtained in this way is filtered, washed with water to a neutral pH, then washed with ethanol and with diethyl ether in order to produce after drying 8.8 g (53%) of a white solid, m.p. 110° C.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[N:10][CH:11]=1.C(O)(=O)C.[BH4-].[Na+]>O>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[N:10][CH:11]=1
Reactant: Cc1ccc(OCc2ccc(/C=C/[N+](=O)[O-])cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(OCc2ccc(CC[N+](=O)[O-])cc2)nc1
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
To a dimethyl sulfoxide (40.0 mL) solution of 5-methyl-2-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine (3.50 g, 12.9 mmol) described in Manufacturing Example 44-1-3 and acetic acid (3.50 mL) was added sodium borohydride (822 mg, 20.6 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 10 minutes. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (1.91 g, 54.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH2:27][C:28]1[S:29][CH:30]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:32]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CC(N(C)C)=O.C(OCC)(=O)C>[C:33]([C:31]1[N:32]=[C:28]([NH:27][C:17]([C:16]2[CH:20]=[CH:21][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:14][CH:15]=2)=[O:18])[S:29][CH:30]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: CC(C)(C)c1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nc(C(C)(C)C)cs4)cc3)c(Cl)cc21
Temperature: 50 °C
Yield: 64.7 %

Procedure:
4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (53 mg, 0.141 mmol) and 2-amino-4-tert-butylthiazole (44.0 mg, 0.281 mmol) in DMA were treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.9 mg, 0.281 mmol) followed by 1-hydroxy-7-azabenzotriazole (19.1 mg, 0.141 mmol) at ambient temperature. The reaction was heated to 50° C. for 14 hours. The reaction was diluted with ethyl acetate, washed with 1 N HCl, saturated aqueous bicarbonate, and brine. The ethyl acetate layer was dried with sodium sulfate and the product purified on SP1 (20 to 65% Ethyl acetate/hexane) to provide the desired compound (47 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31]C)=[C:6]([C:8]([CH3:30])([CH3:29])[CH2:9][C:10]([C:25]([F:28])([F:27])[F:26])([OH:24])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH3:23])=[N:18]3)[CH:7]=1.B(Br)(Br)Br.C(Cl)Cl.CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([C:8]([CH3:29])([CH3:30])[CH2:9][C:10]([C:25]([F:26])([F:27])[F:28])([OH:24])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH3:23])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3O)C(F)(F)F)cccc2n1
Yield: 66.7 %

Procedure:
Analogously to Example 35, 153 mg (0.34 mmol) of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol in 17 ml of CH2Cl2 is reacted with 6.8 ml of 1M boron tribromide-CH2Cl2 solution. After chromatography on silica gel with hexane-ethyl acetate (0-55%), 99 mg of the product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([C:18]([O:20]CC)=[CH2:19])=[CH:17][C:12]=3[C:11]3=[N:23][CH:24]=[N:25][N:10]3[C:9]2=[O:26])=[CH:5][CH:4]=1.Cl.[OH-].[Na+]>O1CCOCC1>[C:18]([C:16]1[CH:15]=[N:14][C:13]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[C:9](=[O:26])[N:10]3[N:25]=[CH:24][N:23]=[C:11]3[C:12]=2[CH:17]=1)(=[O:20])[CH3:19]
Reactant: C=C(OCC)c1cnc2c(c1)c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(C)=O)cnc32)cc1
Yield: 89.5 %

Procedure:
6-(4-Methoxybenzyl)-9-(1-ethoxyvinyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (147 mg, 0.39 mmol) was suspended in dioxane (6 ml) and 6 N hydrochloric acid (3 ml) and stirred for 4 hours. The mixture was basified to pH 11 with 1 N sodium hydroxide and extracted with DCM (3×15 mL). The combined extracts were dried (MgSO4) and concentrated to afford 122 mg (90%) of the ketone as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=O)=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[O:12])[N:7]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][C:34]([N:37]3[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38]3)=[O:36])=[CH:31][CH:32]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CC(=O)O)cc2)n1
Reactant: O[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CC(=O)N3CC[C@H](O)C3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (4-{3-tert-butyl-5-[({[4-(pyridin-4-yloxy)phenyl]amino}carbonyl)-amino]-1H-pyrazol-1-yl}phenyl)acetic acid (150 mg, 0.31 mmol), (S)-3-pyrrolidinol (54 mg, 0.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl, 71 mg, 0.37 mmol), 1-hydroxybenzotrazole hydrate (HOBT, 50 mg, 0.37 mmol), and triethylamine (0.09 mL, 0.62 mmol) in THF/CH2Cl2 (1/1, 6 mL) was stirred at room temperature overnight. The mixture was evaporated at reduced pressure, and the residue was dissolved in CH2Cl2/MeOH and purified by MPLC (EtOAc/Hexane/MeOH). 1H-NMR (DMSO-d6) δ 9.13 (s, 1H), 8.04 (m, 3H), 7.50-7.34 (m, 6H), 7.07 (d, J=8.9 Hz, 2H), 6.85 (dd, JJ=1.8 Hz, 4.8 Hz, 2H), 6.35 (s, 1H), 4.97 (dd, JJ=3.8 Hz, 44.1 Hz, 1H), 4.27 (broad d, J=30.7 Hz, 1H), 3.70-3.56 (m, 4H), 3.44-3.27 (m, 2H), 1.95-1.73 (m, 2H), 1.27 (s, 9H); MS LC-MS [M+H]+=555.2, RT=2.28 min.
Reaction SMILES: C(OC([CH:8]1[S:20][C:11]23[CH:19]=[CH:18][CH:17]=[CH:16][C:12]2=[N:13][CH2:14][CH2:15][CH:10]3[CH:9]1[C:21]([OH:23])=O)=O)(C)(C)C.[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O.O>[S:20]1[C:11]23[CH:19]=[CH:18][CH:17]=[CH:16][C:12]2=[N:13][CH2:14][CH2:15][CH:10]3[CH:9]([C:21]([N:24]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:8]1
Reactant: CC(C)(C)OC(=O)C1SC23C=CC=CC2=NCCC3C1C(=O)O
Reactant: C1CNCCNC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(C1CSC23C=CC=CC2=NCCC13)N1CCCNCC1
Temperature: 50 °C
Yield: 79.2 %

Procedure:
In 5 ml of dimethylformamide were dissolved 0.32 g of 2-tert-butoxycarbonyl-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboxylic acid and 0.2 g of hexahydro-1H-1,4-diazepine and after adding thereto 3 ml of a dimethylformamide solution of 0.33 g of diphenylphosphorylazide, the mixture was stirred overnight. To the reaction mixture was added 50 g of ethyl acetate and the mixture was washed twice with an aqueous 5% sodium hydrogencarbonate solution and then twice with a saturated sodium chloride solution, and thereafter dried with sodium sulfate. After filtering away sodium sulfate, 5 ml of a mixture of 1N hydrochloric acid in ethyl acetate were added to the filtrate and the mixture was heated to 50° C. for one hours. After distilling off ethyl acetate under reduced pressure, the residue formed was dissolved in 30 ml of water and the solution was washed thrice with 10 ml of ethyl ether. The aqueous layer was adjusted to pH 12 with an aqueous solution of 5N sodium hydroxide and after adding thereto 1 g of sodium chloride, the reaction mixture was extracted thrice with chloroform. The chloroform layer was dried by magnesium sulfate and then the residue formed was purified by silica gel thin layer chromatography (solvent: ethyl acetate and methanol of 10:1). Then, 2 ml of a mixture of 1N hydrochloric acid in ethyl acetate was added to the product and crystals thus deposited were collected by filtration to provide 0.24 g (yield of 62%) of hexahydro-1-(1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carbonyl)-1H-1,4-diazepine.di-hydrochloride. (See Table 9-1, Table 10-1).
Reaction SMILES: [OH-].[K+].O.[C:4]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH2:13])=[CH:10][CH:9]=1)(=O)[CH3:5].[CH2:16](Br)C=C>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:4]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH2:13])=[CH:10][CH:9]=1)[CH:5]=[CH2:16]
Reactant: C=CCBr
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C=CCOc1ccc(C=C)cc1
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
To a 4-necked, nitrogen swept, 2 liter glass reaction vessel equipped with a mechanical stirrer, double-walled condenser, thermocouple and pressure compensating addition funnel is added 1,4-dioxane (600 mls), potassium hydroxide (112.0 g, 2.00 moles) and water (39 g). The mixture is stirred and cooled to 10° C. at which time 4-acetoxystyrene (162.0 g, 1.00 moles) is added over approximately 5 minutes. The mixture is stirred for a further 1.5 hour and cooled to 5° C. A solution of allylbromide (133.1 g, 1.10 moles) in 1,4-dioxane (50 mls) is added dropwise over 15 minutes and the reaction mixture is stirred for a further 1.5 hours, while the temperature is maintained between 5° and 10° C. The stirred mixture is gradually heated to 60° C. Heating and stirring are continued at this temperature for a further 2.5 hours. On cooling the mixture is filtered and most of the solvent is removed under reduced pressure. The residue obtained is dissolved in toluene (300 mls) and the solution washed with 4×300 ml portions of water, dried over sodium sulfate and the solvent distilled under reduced pressure to yield crude 4-allyloxystyrene in high yield.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH2:27][C:28]([F:31])([F:30])[F:29])[S:11]([CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)(=[O:13])=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CN>CO>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH2:27][C:28]([F:31])([F:30])[F:29])[S:11]([CH2:14][CH2:15][NH2:16])(=[O:12])=[O:13])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(N(CC(F)(F)F)S(=O)(=O)CCN2C(=O)c3ccccc3C2=O)CC1
Agent: CN
Solvent: CO
Product: CC(C)N1CCC(N(CC(F)(F)F)S(=O)(=O)CCN)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
156.0 mg (0.27 mmol) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-(2,2,2-trifluoro-ethyl)-amide were dissolved in 5 ml MeOH. 2.98 ml (22 equiv.) of a 2 M methylamine-solution in MeOH were added and the reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure to give crude 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-(2,2,2-trifluoro-ethyl)-amide.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([S:9][C:10]2[S:14][C:13]([CH2:15][CH2:16][NH:17][OH:18])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.C[Si]([N:25]=[C:26]=[O:27])(C)C>O1CCOCC1>[OH:18][N:17]([CH2:16][CH2:15][C:13]1[S:14][C:10]([S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)=[CH:11][CH:12]=1)[C:26]([NH2:25])=[O:27]
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCCc1ccc(Sc2cccc(C(F)(F)F)c2)s1
Solvent: C1COCCO1
Product: NC(=O)N(O)CCc1ccc(Sc2cccc(C(F)(F)F)c2)s1
Reaction time: 2 h

Procedure:
To a solution of N-[5-(3-trifluoromethylphenylthio)thien-2-ylethyl]hydroxylamine (7.6 g) in dioxan (70 ml) at room temperature under nitrogen, was added trimethylsilylisocyanate (5.48 g) and the reaction mixture stirred for 2 hours. The solution was quenched with saturated aqueous ammonium chloride, extracted with ether (2×100 ml), dried over MgSO4, evaporated under reduced pressure to give a yellow oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using ether to give a white solid, recrystallised from ether-petroleum ether, m.p. 124°-126° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[OH-].[Na+].Cl.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[CH:34]=[CH:33][C:32](Br)=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:15]12[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[CH:34]=[CH:33][C:32]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[CH2:2][OH:1])=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2
Reactant: OCc1ccccc1B(O)O
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(-c3ccccc3CO)ccc2o1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
110 mg (0.73 mmol) of 2-(hydroxymethyl)phenylboronic acid and 1.46 ml of 1N sodium hydroxide solution are added to a mixture of 170 mg (0.49 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 35 mg (0.05 mmol) of PdCl2(dppf) in 2 ml of DMF. The reaction mixture is heated at 85° C. overnight. The solvent is removed under reduced pressure. Addition of a mixture of 1N sodium hydroxide solution and ethyl acetate to the residue is followed by extraction of the aqueous phase once more with ethyl acetate. The combined organic phases are washed twice with each of 1N sodium hydroxide solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated in a rotary evaporator under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with DMF, again with methanol, with dichloromethane, again with methanol, with water and finally with methanol again. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. 140 mg (76% of theory) of the title compound are isolated.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([N:12]=[C:13]=[S:14])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(Cl)Cl>[C:1]([C:3]1[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([NH:12][C:13]([NH:18][CH2:17][CH2:16][NH2:19])=[S:14])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2]
Reactant: NCCN
Reactant: Cc1c(N=C=S)ccc2c(C#N)c[nH]c12
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)ccc2c(C#N)c[nH]c12
Reaction time: 0.5 h

Procedure:
To a solution of 3-cyano-6-isothiocyanato-7-methylindole (0.152 g, 0.713 mmol) in methylene chloride (30 mL) is added ethylenediamine (0.286 mL, 4.28 mmol). The milky white mixture is stirred for 30 minutes followed by removal of the volatile organics by rotary evaporation. The residue is taken up in 10% methanol/methylene chloride, causing a precipitate to form. This mixture is filtered (solid is saved), and the filtrate is directly applied to a silica gel column. The mixture is separated using 15% methanol (ammonium hydroxide treated)/methylene chloride as eluent. The product containing fractions are combined with the previous precipitate and the solvents removed by rotary evaporation to yield 0.214 g of slightly impure 3-cyano-6-[N'-(2-aminoethyl)thioureido]-7-methylindole as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[CH:9]1([NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[C:27](F)[CH:26]=[CH:25][C:24]=3[N+:30]([O-:32])=[O:31])[CH:20]=2)=[O:14])[CH2:11][CH2:10]1>>[CH:9]1([NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[C:27]([N:6]4[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]4)[CH:26]=[CH:25][C:24]=3[N+:30]([O-:32])=[O:31])[CH:20]=2)=[O:14])[CH2:11][CH2:10]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2C[C@@H](C)N[C@@H](C)C2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials cis-2,6 dimethylpiperazine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 1.03 (d, 6H), 2.28 (s, 3H), 2.40 (t, 2H), 2.79 (m, 3H), 3.94 (d, 2H), 7.05 (m, 2H), 7.28 (d, 1H), 7.55 (d, 1H), 8.01 (m, 2H), 8.36 (s, 1H), 9.87 (s, 1H); Mass Spectrum: M+H+ 452.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].Cl[CH2:10][C:11](Cl)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:8]1[CH2:10][C:11](=[O:12])[NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]1=2
Reactant: Nc1cnccc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2ccncc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
In a 500 ml flask equipped with a reflux apparatus, 3-amino-pyridin-4-ol (7.8 g, 71 mmol) was dissolved in N,N-dimethyl formamide (350 ml). To the reaction solution was added chloroacetyl chloride (6.2 ml, 78 mmol) dropwise at room temperature and then stirred at room temperature for 30 minutes. Potassium carbonate (24 g, 177 mmol) was added thereto and the mixture was heated at 100□ for 40 hours. After completion of the reaction, water was added thereto. The mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by recrystallizing from solvents of ethyl acetate and n-hexane to obtain white solid (5.6 g, 53%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH3:15])=[CH:11][CH:12]=2)[CH:7]([CH3:16])[CH2:6][C:5]1([CH3:18])[CH3:17])(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH3:15])=[CH:11][CH:12]=2)[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:16])[CH2:6][C:5]1([CH3:17])[CH3:18])(=[O:3])[CH3:2]
Reactant: CCc1ccc2c(c1)C(C)CC(C)(C)N2C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Friedel-Crafts alkylation of benzene (10 ml) with 1-acetyl-6-ethyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (410 mg) in the presence of AlCl3 (710 mg) was performed according to the method described in example 3.
Reaction SMILES: Cl.[O:2]1CCO[CH:3]1[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1>C1COCC1.O>[F:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[OH:13])[CH:3]=[O:2]
Reactant: Oc1ccc(C2OCCO2)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(O)c(F)c1
Yield: 95.2 %

Procedure:
A solution of 1N HCl (1 mL) and 4-[1,3]dioxolan-2-yl-2-fluoro-phenol (250 mg, 1.35 mmol) in THF (2 mL) was stirred, at room temperature for 1 hour. The mixture was diluted with water and extracted with methylene chloride (4×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum. The residue was chromatographed (silica gel, hexanes/ethyl acetate 1:1) to produce 3-Fluoro-4-hydroxy-benzaldehyde as a white solid (180 mg, 95%). 1H-NMR (CDCl3, 200.15 MHz): 9.84 (d, 1H, J=2.4), 7.68–7.59 (m, 2H), 7.15 (t, 1H, J=8.5), 6.5 (sa, 1H).