Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH:27]([F:29])[F:28])[CH:23]=[CH:22][C:21]=1B(O)O.CCOC(C)=O.O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([O:26][CH:27]([F:28])[F:29])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: OB(O)c1ccc(OC(F)F)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=[N+]([O-])c1c(-c2ccc(OC(F)F)cc2Cl)ccnc1OCc1ccccc1
Yield: 68 %

Procedure:
To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (6.59 g, 24.9 mmol) in DME/H2O, was added 2-chloro-4-difluoromethoxy-phenylboronic acid (Wilde, et al. WO 99/01454) (5.54 g, 24.9 mmol), Ba(OH)2 8H2O (7.86 g, 24.9 mmol), and Pd(PPh3)2Cl2 (1.01 g, 1.45 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H2O (500 mL). The EtOAc layer was washed with H2O, brine, dried Na2SO4, filtered and concentrated in vacuo to give 6.9 g (68%) of 2-benzyloxy-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridine as a viscous oil; MS(AP) m/z 408.9 [(M+H)+, 100].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.Br[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(#N)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:26][C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:5][C:4]=2[N:3]=1
Reactant: O=C(CBr)N1CCOCC1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(OCC(=O)N4CCOCC4)ccc3c2n1CC(C)(C)O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A mixture of 4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (prepared as described above, 750 mg, 2.27 mmol), 4-(bromoacetyl)morpholine (565 mg, 2.72 mmol), and cesium carbonate (2.22 g, 6.81 mmol) in DMF (30 mL) was heated at 75° C. overnight. The reaction mixture was allowed to cool and was poured into water (300 mL). After 30 minutes, the solution was extracted with chloroform (6×75 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to dryness. The resulting solid was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-35% methanol/dichloromethane (1:10) in dichloromethane) The appropriate fractions were combined and concentrated to yield an off white solid that was slurried in boiling acetonitrile for 15 minutes. The slurry was allowed to cool with stirring. The solid was isolated by filtration and dried to yield 797 mg of 1-[4-amino-2-(ethoxymethyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white solid, mp 209-211° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])[C:25](F)(F)F)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].C1COCC1.[CH:39]1[CH:43]=[C:42](CC(Cl)=O)[S:41][CH:40]=1>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])[CH2:25][C:40]4[S:41][CH:42]=[CH:43][CH:39]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Reactant: O=C(Cl)Cc1cccs1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (250 mg, 0.56 mmol) and 1M LiOH (1.30 mL, 1.39 mmol) in 10:1 THF:H2O (5 mL) was heated at 50° C. overnight. After removal of THF by rotary evaporation, the reaction mixture was redissolved in EtOAc and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4. Following filtration, the solvent was removed by rotary evaporation. After high vacuum removal of the residual solvent, the crude mixture was dissolved in THF (5 mL) and to this was added thiophene-2-acetylchloride (0.10 mL, 0.84 mmol). After overnight stirring, water (0.5 mL) was added and THF removed by rotary evaporation. The reaction mixture was redissolved in DCM (25 mL) washed with saturated NaHCO3 (10 mL), water (10 mL) and brine (10 mL). Organics were dried over MgSO4, filtered and filtrate concentrated under reduced pressure to afford the desired amide (210 mg, 79%) as an off-white solid. ES-LC/MS m/z=476 [M+H]−.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[CH3:3].[F:5][C:6]([F:13])([F:12])[C:7]([F:11])=[C:8]([F:10])[F:9]>>[F:5][C:6]([F:13])([F:12])[CH:7]([F:11])[C:8]([F:10])([F:9])[C:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)C
Reactant: FC(F)=C(F)C(F)(F)F
Product: CC(C)(C)C(F)(F)C(F)C(F)(F)F

Procedure:
Isobutane (1.98 g., 34.2 mmole) and hexafluoropropene (1.71 g., 11.4 mmole) were heated at 295° for 4 days to give: (i) isobutane (1.42 g., 24.4 mmole; 71% recovery); (ii) hexafluoropropene (0.51 g., 3.4 mmole; 30% recovery); (iii) 1,1,1,2,3,3-hexafluoro-4,4-dimethylpentane (CH3)3C. CF2. CHF. CF3 (1.39g., 6.7 mmole; 84% based on C3F6 consumed) (Found: C, 40.6; H, 4.7%; M, 209. C7H10F6 required C, 40.4; H, 4.8%; M, 208), b.p. 101° C. Similar reactions carried out at 210° C, 260° C and 330° C gave respectively 2% 43% and 51% conversions to 1,1,1,2,3,3-hexafluoro-4,4-dimethylpentane (100%, 80% 52% yields based on C3F6 consumed).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.C(N(CC)CC)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([N:6]=[C:22]=[O:24])=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCOc1cc(N=C=O)c(F)cc1Cl

Procedure:
To a stirred solution of 4-chloro-2 fluoro-5-[(2-propynyl)oxy]-aniline (5.0 gm) and triethylamine (5.1 gm) in CH2Cl2 (100 mL) under N2, at 10° C. (ice-bath) was added triphosgene portionwise. The solution was heated to reflux for 5 hours. The solution was evaporated under vacuum and suspended in Et2O (200 mL). The suspension was filtered and the filtrate evaporated to dryness to give the title compound as a white solid (4.68 gm), 83%; IR (nujol, cm-1): 3295 (C≡C) and 2257 (N=C=O). This crude product was used as such in the next reaction.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.C1N=CN([C:14](N2C=NC=C2)=[O:15])C=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1.O>CN(C)C=O>[CH3:1][N:2]1[C:6]([NH:7][C:14]([NH:21][C:22]2[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=2[CH3:44])[O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[N:34]=3)[N:31]=2)=[O:15])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(N)n(C)n1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NC(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
To a solution of 1,3-dimethyl-1H-pyrazol-5-amine (104 mg, 0.93 mmol) in N,N-dimethylformamide (4.0 mL) was added N,N-carbonyldiimidazole (150 mg, 0.93 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethanol/ethyl acetate=1/20→1/10) to give the title compound (58 mg, 20%) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:14]=[CH:13][C:7]2[S:8][C:9]([CH3:12])([CH3:11])[S:10][C:6]=2[CH:5]=1)O.[BrH:15].[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[Br-:15].[CH3:11][C:9]1([CH3:12])[S:8][C:7]2[CH:13]=[CH:14][C:4]([CH:2]([P+:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:1])=[CH:5][C:6]=2[S:10]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Br
Reactant: CC(O)c1ccc2c(c1)SC(C)(C)S2
Solvent: CC#N
Product: CC(c1ccc2c(c1)SC(C)(C)S2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 100.1 %

Procedure:
28.9 g of aluminum chloride were added portionwise at 0° C. to 16.8 ml of acetyl chloride in 360 ml of methylene chloride. After an additional 30 minutes at 0° C., a solution of 35.9 g of 2,2-dimethyl-1,3-benzodithiol in 180 ml of methylene chloride was slowly added dropwise and the mixture was stirred at 0° C. for an additional 12 hours and thereafter at 20° C. for 5 hours. Thereafter, the mixture was poured on to ice, extracted with methylene chloride and the extracts were washed neutral with dilute sodium hydroxide solution and water, dried over sodium sulfate and evaporated. After recrystallization from methanol/water, there were obtained 41.8 g of 2,2-dimethyl-1,3-benzodithiol-5-yl methyl ketone, melting point 75°-76° C. Then, 41.8 g of this ketone were dissolved in 1 l of ethanol, cooled to 0° C. and 7 g of sodium borohydride were added portionwise. Thereafter, the mixture was stirred at 20° C. for 3 hours, evaporated in a vacuum to a large extent, 200 ml of water were added, the mixture was adjusted slowly to pH 4 with 1N sulfuric acid while cooling and extracted three times with ether. The extracts were washed with water, dried and evaporated, and 42.6 g of α,2,2-trimethyl-1,3-benzodithiol-5-methanol were obtained. Thereafter, 39.5 g of this alcohol were reacted with 65.9 g of triphenylphosphine hydrobromide in 500 ml of acetonitrile and worked-up as described in Example 8 and 96.3 g of [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide were obtained. Then, 17.0 g of this phosphonium salt were reacted with methyl 4-formyl-benzoate in analogy to Example 8. After working-up and recrystallization from ethyl acetate/hexane, there were obtained 4.9 g of methyl p-[(E)-2-(2,2-dimethyl-1,3-benzo-dithiol-5-yl)propenyl]benzoate in the form of colorless crystals, melting point 86°-87° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[N+]1([O-])CC[O:24]CC1.O>C(#N)C>[CH:2]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:24]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(CBr)c1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2ccccc2)c(C=O)c1
Reaction time: 4 h
Yield: 66.7 %

Procedure:
In 100 ml of acetonitrile was dissolved 9.3 g of ethyl 2-(bromomethyl)biphenyl-4-carboxylate, and 7.0 g of N-methylmorpholine-N-oxide was added thereto at room temperature, followed by 4 hours of stirring. Water was added to the reaction solution, which was then extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate. After the solvent was removed by evaporation, the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 4.94 g of ethyl 2-formylbiphenyl-4-carboxylate as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>CN(C)C=O.C(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)s1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)s1
Yield: 99.1 %

Procedure:
A mixture of 5-bromothiophene-2-carboxylic acid (300 mg 1.45 mmol), thionyl chloride (423 μL, 5.80 mmol), and N,N-dimethylformamide (1 drop) was dissolved in chloroform (3 mL), and refluxed for 1 hour. After cooling down, the reaction mixture was concentrated under reduced pressure to give the titled reference compound (324 mg) as a pale yellow solid. (Yield 99%)
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[C:10]([C:14]([C:16]2[C:24]3[C:23]([Cl:25])=[N:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)=[O:15])[CH:11]=[N:12][CH:13]=1>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([C:14]([C:16]2[C:24]3[C:23]([Cl:25])=[N:22][CH:21]=[N:20][C:19]=3[N:18]([CH3:1])[CH:17]=2)=[O:15])[CH:11]=[N:12][CH:13]=1
Reactant: O=C(c1cncc(Br)c1)c1c[nH]c2ncnc(Cl)c12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)c2cncc(Br)c2)c2c(Cl)ncnc21
Reaction time: 0.5 h

Procedure:
Cs2CO3 (2.32 g, 7.11 mmol) was added to a suspension of (5-Bromo-pyridin-3-yl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (1.0 g, 5.93 mmol) in DMF (60 mL) at room temperature. The resulting mixture was stirred for 30 min. Mel (1.01 g, 7.11 mmol) was added and the reaction and stirred for 2 h at room temperature. The reaction mixture was quenched with water (30 mL) and extracted with hot EtOAc (3×50 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (ethyl acetate/hexanes 2:8-7:3) provided a solid. The solid was triturated with EtOAc to provide the title compound as an off white solid (1.52 g, 73%). MS: 351.9/353.9 (MH+); HPLC Rf: 4.45 min. (HPLC method 4).
Reaction SMILES: CC(C)([O-])C.[Na+].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C@H:17]1[CH2:20][C@H:19]([NH2:21])[CH2:18]1.Cl[C:23]1[C:28]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=[CH:25][N:24]=1.O1CCOCC1>O.[Pd](Cl)Cl>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C@H:17]1[CH2:18][C@H:19]([NH:21][C:23]2[C:28]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:20]1.[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C@H:17]1[CH2:18][C@H:19]([N:21]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:28]3[CH2:29][C:30]2=[O:31])[CH2:20]1
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: COC(=O)Cc1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Cc1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Product: O=C1Cc2cccnc2N1[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium tert-butoxide (0.844 mL, 6.89 mmol), [dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine]2-(2-aminoethyl)phenyl)palladium(II) chloride (125 mg, 0.157 mmol), trans-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (intermediate 11, 687 mg, 3.13 mmol), methyl 2-(2-chloropyridin-3-yl)acetate (640 mg, 3.45 mmol) and dry dioxane (5 mL) were sealed in a microwave vessel under argon. The mixture was stirred for 4 hours at room temperature. The reaction mixture was diluted with water (mL) and extracted with ethyl acetate. The organic extract was washed with water and dried over magnesium sulfate. Evaporation in vacuo gave the crude material as a tan solid. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g, hexane to ethyl acetate gradient), to provide methyl 2-(2-((trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)amino)pyridin-3-yl)acetate (210 mg, 0.570 mmol, 18.19% yield) and 1-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (24 mg, 0.071 mmol, 2.277% yield) as white solid. M+1: 337. 1H NMR (400 MHz, MeOH) δ ppm 2.44-2.53 (m, 2 H) 3.48-3.57 (m, 2 H) 3.62 (s, 2 H) 4.62-4.70 (m, 1 H) 5.30 (quin, J=8.66 Hz, 1 H) 7.03-7.13 (m, 2 H) 7.25-7.31 (m, 1 H) 7.48 (d, J=8.02 Hz, 1 H) 7.61-7.66 (m, 2 H) 8.22 (d, J=4.69 Hz, 1 H)
Reaction SMILES: [CH2:1]([CH:4]1[NH:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([NH2:16])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C([C@@H]1N[C@@H](C2C=CC=CC=2)[C@@H](N)CC1)CC.C([C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1)CC.[CH3:49][O:50][C:51]1[CH:60]=[C:59]2[C:54]([N:55]([CH3:63])[C:56](=[O:62])[CH:57]3[CH2:61][CH:58]32)=[CH:53][C:52]=1[CH:64]=O>>[CH3:49][O:50][C:51]1[CH:60]=[C:59]2[C:54]([N:55]([CH3:63])[C:56](=[O:62])[CH:57]3[CH2:61][CH:58]32)=[CH:53][C:52]=1[CH2:64][NH:16][CH:7]1[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[NH:9][CH:8]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)C1CC21
Reactant: CCCC1CCC(N)C(c2ccccc2)N1
Agent: CCC[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Agent: CCC[C@H]1CC[C@H](N)[C@H](c2ccccc2)N1
Product: CCCC1CCC(NCc2cc3c(cc2OC)C2CC2C(=O)N3C)C(c2ccccc2)N1

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-propyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S)-6-propyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-propyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde [or (1S,1aR)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde or (1R,1aS)-6-Methoxy-3-methyl-2-oxo-1a,2,3,7b-tetrahydro-1H-3-aza-cyclopropa[a]naphthalene-5-carbaldehyde].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([O:1][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Cc1ccc(O)cn1
Product: Cc1ccc(OC(=O)N(C)c2ccccc2)cn1

Procedure:
The title product was prepared from 3-hydroxy-6-methyl-pyridine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (79%, colourless oil). HPLC-MS: m/z=243.1 (M+1); Rt: 2.24 min.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[CH3:18][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][C:8]1=[O:17]
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2ccc(Cl)cc2C1c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: CC1(c2ccccc2)C(=O)Nc2ccc(Cl)cc21
Temperature: 50 °C

Procedure:
10 g of 3-phenyl-5-chlorooxindole were dissolved in 100 ml of acetone and 20 ml of water, 2.9 g of potassium carbonate and 2.9 ml of methyl iodide were added and the mixture was warmed at 50° C. for 3 hours and concentrated; water was added to the residue, which was extracted with ethyl acetate, and the extract was dried over magnesium sulfate, and the solvent was removed. The residue was recrystallized from ethanol. Melting point 180°-181° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([OH:21])=O)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH:25]([CH3:29])[NH:24]1.C(N=C=NC(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[Cl:49]CCl>>[ClH:49].[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([N:27]3[CH2:26][CH:25]([CH3:29])[NH:24][CH:23]([CH3:22])[CH2:28]3)=[O:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Reactant: CC1CNCC(C)N1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: COc1cccc2c(C(=O)N3CC(C)NC(C)C3)cn(CC3CCCCC3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(cyclohexylmethyl)-7-methoxy-indole-3-carboxylic acid (0.25 g, 0.87 mmol, prepared following the method in Example 1) and 2,6-dimethylpiperazine (0.12 g, 1.05 mmol) in dichloromethane (10 ml) was added diisopropylcarbodiimide (0.16 ml, 1.05 mmol) and 1-hydroxybenzotriazole (0.01 g, 0.09 mmol). The mixtures was stirred at room temperature for 18 h. The mixture was washed with 5 M sodium hydroxide (2×10 ml), dried with magnesium sulfate and evaporated. The residue was purified by flash chromatography eluting with 5-10% (v/v) methanol in dichloromethane to afford the title compound (free base) as a colourless oil. The free base (0.15 g) was dissolved in diethyl ether (3 ml) and treated dropwise with 2 M hydrochloric acid in diethyl ether (1 ml). The resulting precipitate was collected by filtration, washed with diethyl ether (15 ml) and dried under reduced pressure to afford the title compound (1:1 hydrochloric acid salt) as a colourless solid (0.15 g, 0.36 mmol). 1H NMR (400 MHz, CD3OD) δH 0.98-1.26 (5H, m) 1.32 (6H, d, J 6.5), 1.56 (2H, brd, J 12.0), 1.62-1.90 (4H, m), 3.06 (2H, dd, J 14.5, 11.5), 3.39-3.50 (2H, m), 3.95 (3H, s), 4.26 (2H, d, J 7.5), 4.52 (2H, br d, J 13.5), 6.77 (1H, d, J 7.5), 7.1 (1H, t, J 8.0), 7.24 (1H, d, J 8.0), 7.54 (1H, s); EIMS: m/z 384.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8][C:7](=[O:17])[C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH:7]([OH:17])[C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: COc1c([N+](=O)[O-])cc(Cl)c2c1C(=O)C[C@@H](NC(C)=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c([N+](=O)[O-])cc(Cl)c2c1C(O)C[C@@H](NC(C)=O)CC2
Reaction time: 0.25 h

Procedure:
N—((S)-4-Chloro-1-methoxy-2-nitro-9-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide (100 mg; 0.3 mmol), of Example 632f, in Methanol (10 mL) was treated with Sodium tetrahydroborate (30 mg, 0.8 mmol) neat at rt. After 15 minutes, a second portion of Sodium tetrahydroborate (30 mg, 0.8 mmol) was added to the reaction mixture. After 30 minutes the reaction mixture was treated with water, then extract with Et2O followed by CH2Cl2 (2×). The aqueous phase was treated with 1N KOH and re-extracted with CH2Cl2. The organics were combined, dried over MgSO4, filtered and concentrated to give 210 mg (TW 100 mg) of whitish, crude N—((S)-4-Chloro-9-(R,S)-hydroxy-1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide, which was used without further purification; MS (m/e) 328.97 (M+H).