Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]([CH3:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:13]([N+:28]([O-:30])=[O:29])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].O.O.[OH-].[Li+].Cl>C1COCC1.CO>[CH3:27][C@H:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)=[CH:12][C:13]=1[N+:28]([O-:30])=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC[C@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCC[C@H](C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
Ester 41b (390 mg, 0.94 mmol) was dissolved in 3 ml THF and 15 ml methanol. Water was added with vigorous stirring until the solution remained cloudy, followed by the addition of lithium hydroxide monohydrate (56 mg, 1.30 mmol). After refluxing overnight, the solution was acidified with concentrated HCl and extracted with ether. The organic layer was washed with brine and dried over MgSO4. Evaporation of the solvent yielded 323 mg (86%) of a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH:10]([CH3:11])[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:12])=[O:4].[S-:13][C:14]#[N:15].[K+]>C(O)C>[S:13]([CH2:2][C:3]([N:5]1[CH:10]([CH3:11])[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:12])=[O:4])[C:14]#[N:15]
Reactant: N#C[S-]
Reactant: CC1CCCC(C)N1C(=O)CCl
Agent: [K+]
Solvent: CCO
Product: CC1CCCC(C)N1C(=O)CSC#N
Reaction time: 3 h

Procedure:
1-(α-Chloroacetyl)-2,6-dimethylpiperidine (18.9 grams; 0.1 mol), potassium thiocyanate (18 grams; 0.2 mol) and ethanol (100 ml) were charged into a glass reaction flask equipped with a mechanical stirrier and reflux condenser. The reaction mixture was heated at reflux, with stirring, for a period of about 3 hours. After this time the reaction mixture was cooled and filtered. The ethanol was evaporated under reduced pressure to yield a dark solid. The solid was extracted with two 200 ml portions of hot benzene. The benzene extracts were combined, were filtered and treated with activated charcoal. The benzene solution was then evaporated under reduced pressure to yield a dark colored oil which solidified upon standing. The solidified product then crystallized, to yield 1-(α-thiocyanoacetyl)-2,6-dimethylpiperidine as a pale yellow solid having a melting point of 81° to 82° C. and leaving the following elemental analysis as calculated for C10H16N2OS.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH3:17])[CH2:4][O:5][C:6]1[N:11]=[C:10]([C:12]([O:14]C)=O)[CH:9]=[CH:8][CH:7]=1)[CH3:2].[CH3:18][C:19]#[N:20]>>[CH2:16]([CH:3]([CH2:1][CH3:2])[CH2:4][O:5][C:6]1[N:11]=[C:10]([C:12](=[O:14])[CH2:18][C:19]#[N:20])[CH:9]=[CH:8][CH:7]=1)[CH3:17]
Reactant: CC#N
Reactant: CCC(CC)COc1cccc(C(=O)OC)n1
Product: CCC(CC)COc1cccc(C(=O)CC#N)n1

Procedure:
CH3CN addition to methyl 6-(2-ethylbutoxy)picolinate following the method described in Example 6 gave 3-(6-(2-ethylbutoxy)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (1.2 g, quant.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]([OH:23])=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH:24](I)([CH3:26])[CH3:25].CC([O-])(C)C.[K+].CCOC(C)=O>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(C)I
Reactant: Nc1nc(-c2ccccc2)c(-c2ccc(=O)[nH]c2)nc1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1nc(-c2ccc(=O)[nH]c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic acid (283 mg) was dissolved in DMF (10 ml). To the solution were added i-PrI (172 mg) and t-BuOK (114 mg). The mixture was stirred at 20-30° C. for 2 hours. The reaction mixture was portioned EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO4. Evaporation of solvent gave oily residue. The above residue was purified by chromatography on silica gel (EtOAc only-EtOAc:MeOH=96:4, v/v) to give isopropyl 3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylate as yellow crystal (64 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[F:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:27]2[CH2:28][CH2:29][C@H:25]([F:24])[CH2:26]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: F[C@H]1CCNC1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](F)C1
Temperature: 65 °C
Yield: 100.5 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), (3S)-3-fluoropyrrolidine hydrochloride (0.051 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol) and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated to dryness. The resulting residue was purified on silica gel (eluting with 0 to 30% ethyl acetate in hexane) to give the desired product (0.10 g). LCMS calculated for C15H15ClFN2O (M+H)+: m/z=293.1; Found: 293.0.
Reaction SMILES: [C:1]1([OH:9])(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]1[CH3:7].C1(C)C(O)=CC=CC=1.[F:18][C:19]([F:27])([F:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[O:21]>>[CH3:7][C:2]1[CH:3]=[C:4]([C:20]([OH:21])([C:22]([F:25])([F:24])[F:23])[C:19]([F:27])([F:26])[F:18])[CH:5]=[CH:6][C:1]=1[OH:9]
Reactant: CC1C=CC=CC1(C)O
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccccc1O
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1O

Procedure:
The procedure of Example 1 was essentially repeated, except that the xylenol was replaced with 540 g (5.0 moles) of orthocresol, and gaseous hexafluoroacetone, 83 g (0.5 mole) was added via a glass gas delivery tube reaching below the surface of the well-stirred mixture. At the completion of the reaction, as in Example 1, after recrystallization from hexane, white crystals of 1-methyl-4(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoroethyl)phenol having 99.7% purity and melting at 89.5°-90.5° C. were isolated from the reaction mixture.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH2:13][CH:14]([OH:16])[CH2:15][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[CH2:22][CH3:23]>CN(C=O)C>[CH2:1]([N:8]1[C:12]2[CH2:13][CH:14]([O:16][CH2:21][CH2:22][CH3:23])[CH2:15][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: N#Cc1nn(Cc2ccccc2)c2c1CC(O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOC1Cc2c(C#N)nn(Cc3ccccc3)c2C1

Procedure:
To a solution of 1-benzyl-5-hydroxy-1,4,5,6-tetrahydrocyclo-penta[c]pyrazole-3-carbonitrile-(see Example 9.7, 30 mg, 0.125 mmol) in anhydrous DMF (2 mL) was added sodium hydride (6 mg, 0.15 mmol, 60% dispersion in oil). After stirring for 3 minutes propyl bromide was added (14 μL, 0.15 mmol) and the resulting mixture stirred for an hour. At the end of this time sodium hydride (6 mg, 0.15 mmol, 60% dispersion in oil) and propyl bromide were added. After 30 minutes the reaction was quenched by adding saturated NH4Cl (3 mL). The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by PTLC (SiO2) using 15% ethyl acetate-hexanes to give the desired product.
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:29](=[O:30])[N:28](CC3C=CC(OC)=CC=3OC)[C:27](=O)[C:17]=2[C:18]([O:25][CH3:26])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(O)(C)C.[BH4-].[Li+]>O1CCCC1.CO>[OH:14][C:15]1[C:16]2[C:29](=[O:30])[NH:28][CH2:27][C:17]=2[C:18]([O:25][CH3:26])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: COc1ccc(CN2C(=O)c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc4c3OC)C2=O)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1c2c(c(O)c3ncccc13)C(=O)NC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.1 %

Procedure:
9-Benzhydryloxy-7-(2,4-dimethoxy-benzyl)-5-methoxy-pyrrolo [3,4-g]quinoline-6,8-dione 302 (500 mg, 0.89 mmol) was dissolved in tetrahydrofuran (6.0 ml), water (1.2 ml), and isopropanol (2.4 ml) and cooled to 0° C. Lithium borohydride (LiBH4, 96.9 mg, 4.45 mmol) was then added and the reaction mixture was removed from the ice bath and stirred at room temperature for 2 hours. After quenching with acetic acid (0.5 ml), the reaction mixture was diluted with ethyl acetate, washed with twice with water, once with brine, and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (9.2 ml) and triethylsilane (1.8 ml), and cooled to 0° C. After adding trifluoroacetic acid (3.6 ml), the reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the resulting residue was redissolved in trifluoroacetic acid (10 ml) and triethylsilane (2 ml). It was then warmed to 75° C. and stirred at 75° C. for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped three times with a (1:1) toluene/tetrahydrofuran solution. The resulting residue was triturated three times with a (3:1) hexane/ether mixture. The remaining solid in the filter funnel and reaction flask was dissolved in methanol, combined, and concentrated in vacuo to afford 9-hydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 303 (240 mg, 113%). 1H NMR (d-DMSO) δ 8.84 (dd, 1H), 8.58 (broad, 1H), 8.50 (dd, 1H), 7.60 (m, 1H), 4.60 (s, 2H), 3.94 (s, 3H). MS: 231.1 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>CN(C=O)C>[CH:6]1[CH:7]=[CH:8][C:9]2[NH:1][C:2]3[CH:9]=[N:1][CH:2]=[CH:3][C:3]=3[C:4]=2[CH:5]=1
Reactant: c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: c1ccc2c(c1)[nH]c1cnccc12

Procedure:
Thereby, 0.1 mole of indole derivative was dissolved in DMF and 0.12 mole of the aldehyde was added with stirring. The reaction mixture was stirred at room temperature for 16 hours. After removal of the solvent, the resulting solid was re-crystallised twice in toluene and dried. In a further synthesis step, 0.07 mol of the solid re-crystallised in toluene and dried were dissolved in 600 ml of cumene and reflux-heated with 2.6 grams of Pd/C (10%) in a nitrogen atmosphere for 90 minutes. After addition of 100 ml of ethanol, the hot solution was filtrated, and the coal was extracted three times by 30 ml of hot ethanol. The combined liquid fractions were freed of solvent in vacuum, and the residue was crystallised in toluene to obtain the 1,3-disubstituted derivative of norharman.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[C:11]([O:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[C:21]=4[Cl:33])[CH3:19])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH:36]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH2:37]>C1COCC1>[Cl:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[C:11]([O:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]5[CH2:32][CH2:31][N:30]([CH2:37][CH2:36][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:29][CH2:28]5)[C:21]=4[Cl:33])[CH3:19])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(Cl)ccc32)sc1C(N)=O)c1cccc(OC2CCNCC2)c1Cl
Reactant: C=CS(C)(=O)=O
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(-n2cnc3cc(Cl)ccc32)sc1C(N)=O)c1cccc(OC2CCN(CCS(C)(=O)=O)CC2)c1Cl
Yield: 78.4 %

Procedure:
A solution of 5-{5-chloro-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy}-2-thiophenecarboxamide (Intermediate 12, 112 mg, 0.21 mmol) and methyl vinyl sulfone (22 μL, 0.25 mmol) in 2 mL THF were stirred until the starting material was consumed. The reaction was concentrated onto silica gel and purified by flash column chromatography to give 105 mg of the title compound (78%). 1H NMR (400 MHz, d6-DMSO) δ 8.61 (s, 1H), 7.83 (m, 1H), 7.80 (br s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.36-7.29 (m, 2H), 7.20-7.13 (m, 3H), 7.08 (br s, 1H), 5.95 (m, 1H), 4.48 (m, 1H), 3.25-3.21 (m, 2H), 2.99 (s, 3H), 2.67-2.64 (m, 4H), 2.29 (m, 2H), 1.85 (m, 2H), 1.68 (d, J=6.0 Hz, 3H), 1.62 (m, 2H). HRMS calculated [M+H]+ C28H31Cl2N4O5S2 637.1113, found 637.1120.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.C(Cl)(C([Cl:15])=O)=O>CCOC(C)=O.CN(C=O)C>[Cl:15][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1
Reactant: O=C(O)c1cc(O)ncn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)ncn1
Temperature: 75 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
To a solution of 6-hydroxypyrimidine-4-carboxylic acid (6.0 g, 42.8 mmol) in EtOAc (90 mL) was added (COCl)2 (12 mL) dropwise, followed by a few drops of DMF. The mixture was stirred at 75° C. for 3 h, and then at 25° C. for 16 h. The solvent was evaporated to give the crude 6-chloropyrimidine-4-carboxylic acid (6.3 g, yield: 92.9%). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 6.88 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])CC2C=CC=CC=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Br>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[O:33][C:32]([F:43])([F:42])[F:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)Oc1ccccc1CBr
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: OC(Cc1ccccc1OC(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 2-(trifluoromethoxy)benzyl bromide (available from Fluorochem) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=458.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[OH:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([O:3][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=2)[CH:9]=1
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)Oc2cc(O)ccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To 3.5 g of 2,4-bis(trimethylsilyloxy)-pyridine in 50 ml of methylene chloride was added 2.34 g of p-methylbenzoyl chloride and the mixture was stirred at room temperature for one hour. Following thereafter the general procedure of Example 27, 1.86 g of the title compound was produced in a yield of 59.2%.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:31][C:6]2[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28](O)=[O:29])[CH:23]=4)[CH:17]=3)=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:32])[CH2:3]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(Cl)CCl.O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:1][C:2]1([CH3:33])[CH2:31][C:6]2[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[O:29])[CH:23]=4)[CH:17]=3)=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[S:9][C:5]=2[C:4](=[O:32])[CH2:3]1
Reactant: C1COCCN1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4ccnc(C(=O)O)c4)c3)c2C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4ccnc(C(=O)N5CCOCC5)c4)c3)c2C1
Yield: 48.5 %

Procedure:
A mixture of Example 223 (55 mg, 0.12 mmol), morpholine (12 mL, 0.14 mmol), EDC (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole hydrate (3 mg, 0.02 mmol) in DCM (10 mL) was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (pH 2.5) to give the title compound (31 mg, 49%) as a yellow oil. δH (CDCl3) 8.82 (1H, dd, J 5.1, 0.6 Hz), 8.73 (1H, dd, J 5.1, 0.4 Hz), 8.30 (1H, d, J 1.1 Hz), 8.04 (1H, dd, J 5.1, 1.7 Hz), 7.91 (1H, s), 7.38 (1H, dd, J 4.9, 1.3 Hz), 3.90-3.81 (4H, m), 3.77-3.71 (4H, m), 3.70-3.65 (4H, m), 3.05-2.98 (4H, m), 2.51 (2H, s), 2.47 (2H, s), 1.05 (6H, s). LCMS (ES+) 533.3 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:18]=3[N:19]=2)[CH:11]=[C:10]([Cl:25])[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:25][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:18]=3[N:19]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Oc2nc3cc(Cl)ccc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Cl)cc(Oc2nc3cc(Cl)ccc3s2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
To [3-chloro-5-(5-chloro-benzothiazol-2-yloxy)-phenyl]-carbamic Acid tert-butyl ester (263, 1.17 g, 2.85 mmol) was added trifluoroacetic Acid. The mixture was stirred at ambient temperature for 5 h, at which time TLC showed there was no starting material remained. The mixture was concentrated to dryness under reduced pressure, dissolved in EtOAc. The organic solution was washed with 1N NaOH, washed twice with a brine solution, dried over Na2SO4 and concentrated. The residue was purified by chromatography with CH2Cl2 to give 785 mg of product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)OC2)C1=O.Cl[CH2:46][C:47]1[CH:48]=[C:49]([S:53]([N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)(=[O:55])=[O:54])[CH:50]=[CH:51][CH:52]=1.BrCCCCC>>[N:56]1([S:53]([C:49]2[CH:48]=[C:47]([CH:52]=[CH:51][CH:50]=2)[CH2:46][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])(=[O:54])=[O:55])[CH2:57][CH2:58][O:59][CH2:60][CH2:61]1
Reactant: O=S(=O)(c1cccc(CCl)c1)N1CCOCC1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Solvent: CCCCCBr
Product: O=C1N(Cc2cccc(S(=O)(=O)N3CCOCC3)c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 4-(3-(chloromethyl)phenylsulfonyl)morpholine to replace 1-bromopentane, 1′43-(morpholin-4-ylsulfonyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (40%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 7.73-7.64 (m, 4H), 7.29-7.18 (m, 2H), 7.05 (dd, J=7.3, 5.6 Hz, 2H), 6.52 (s, 1H), 6.11 (s, 1H), 5.09 (ABq, 2H), 4.74 (dd, J=9.3 Hz, 2H), 4.04-4.21 (m, 4H), 3.56 (t, J=4.5 Hz, 4H), 2.84-2.65 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 154.8, 144.2, 141.9, 138.0, 137.9, 134.7, 132.2, 131.6, 130.1, 128.8, 126.7, 125.9, 123.9, 123.3, 121.0, 110.9, 109.5, 98.9, 79.5, 65.2, 64.2, 63.6, 57.3, 45.8, 42.5; MS (ES+) m/z 534.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH:23]=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:18]
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)ccc1F
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1F
Yield: 30 %

Procedure:
The title compound (11 mg, 30%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3-ethoxy-4-fluoro-benzaldehyde. MS: 372.5 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH:14]=O.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1/[CH:14]=[C:24]1\[C:25](=[O:29])[NH:26][C:27]2[C:23]\1=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=2
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COC(=O)C(C)(C)COc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)C(C)(C)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 66.6 %

Procedure:
3-(4-Chloro-2-formyl-phenoxy)-2,2-dimethyl-propionic acid methyl ester (6.7 g, 25 mmol) and 6-Chlorooxindole (4.35 g, 25 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (2 mL, 25 mmol) was added slowly at r.t. The mixture was heated at 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as a yellow solid (Yield: 7 g, 67%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:31])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:31])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccccc1OC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)N2CCOCC2)ccc1C(C)(C)C)c1ccccc1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2-methoxyphenyl)octanamide (prepared as described in Preparation 74F) and morpholine, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32]([N:34]2[CH2:39][CH2:38]O[CH2:36][CH2:35]2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].N1CCCC1>>[CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32]([N:34]2[CH2:35][CH2:36][CH2:38][CH2:39]2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)N3CCOCC3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Solvent: C1CCNC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)N3CCCC3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 4.5 %

Procedure:
The title compound was synthesized using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)morpholine-4-carboxamide, using pyrrolidine as the amine source (4.5% yield). MS m/z=526.5 [M+H], calc 525.69 for C28H43N7O3. 1H NMR (DMSO-d6) δ ppm: 11.77 (s., 1H), 7.98 (s, 1H), 7.62 (d, J=1.0 Hz, 1H), 6.79 (s, 1H), 4.45-4.58 (m, 1H), 4.30 (t, J=1.0 Hz, 2H), 3.85-4.00 (m, 1H), 3.43-3.53 (m, 2H), 3.30-3.36 (m, 2H), 2.61 (t, J=1.0 Hz, 2H), 2.52-2.59 (m, 2H), 2.36-2.47 (m, 5H), 2.01-2.10 (m, 2H), 1.75-1.86 (m, 4H), 1.53-1.65 (m, 2H), 1.43-1.53 (m, 6H), 1.32-1.42 (m, 2H), 1.08 (d, J=6.6 Hz, 6H).