Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)(=O)=O.COC1(C(=O)NC2(C)CCC2)CCN(C2CC3N(C(OCC)=O)C(CC3)C2)CC1.[NH:50]1[CH2:60][CH2:59][CH:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:52][CH2:51]1>>[CH2:57]([O:56][C:54]([CH:53]1[CH2:59][CH2:60][N:50]([CH:6]2[CH2:9][C:8]3([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]3)[CH2:7]2)[CH2:51][CH2:52]1)=[O:55])[CH3:58]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(OS(C)(=O)=O)C2)C1
Agent: CCOC(=O)N1C2CCC1CC(N1CCC(OC)(C(=O)NC3(C)CCC3)CC1)C2
Product: CCOC(=O)C1CCN(C2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)CC1
Yield: 12.5 %

Procedure:
tert-Butyl 2-[(methylsulfonyl)oxy]-6-azaspiro[3.4]octane-6-carboxylate isomer 1 (1.79 g, 5.73 mmol) and ethyl isonipecotate (4.49 g, 28.62 mmol) were heated together to 65° C. for 5 days. The reaction mixture was reduced in volume in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 100 g, 40-63 μm, 60 A, 50 mL per min, gradient 1% to 4.5% MeOH in DCM]) to give tert-butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.264 g, 12.5%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: COc1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccccc3OC)c2cc1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (102 mg) and commercially available 2-methoxyphenol (0.5 ml) were mixed and stirred at 150° C. for 8 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting first with hexane/ethyl acetate and then with chloroform/methanol to obtain 76 mg of the title compound (yield: 54%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]([CH3:57])[C@H:52]1[CH2:56][CH2:55][NH:54][CH2:53]1>CN(C)C=O>[CH3:50][N:51]([CH3:57])[C@H:52]1[CH2:56][CH2:55][N:54]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=5)=[O:49])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:53]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 35.8 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (60.8 mg) in N,N-dimethylformamide (1.0 ml) was added (3S)-(−)-3-dimethylaminopyrrolidine (41.7 mg), followed by stirring at room temperature for 7 hr. The reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:2, and the precipitated solid was collected by filtration. This was dried under aeration to provide the titled compound as white powder (18.5 mg, 35.8%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=2[NH:4][C:3]1=S.O=S(Cl)[Cl:17]>>[Cl:17][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=2[N:4]=1
Reactant: Cn1c(=S)[nH]c2cc([N+](=O)[O-])ccc21
Reactant: O=S(Cl)Cl
Product: Cn1c(Cl)nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
The compound 1-Methyl-5-nitro-1,3-dihydro-benzoimidazole-2-thione (5.8 g, 27.9 mmol) was heated to reflux with SOCl2 (30 ml) overnight. The reaction mixture was cooled to room temperature and poured into 300 ml of ice water and extracted with CH2Cl2. The organic layers was washed with 10% NaHCO3 water solution, brine, dried over Na2SO4 and concentrated to give the title compound as a yellow solid. MS (ESI) m/z=212 [M+H].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH3:13])([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].O>C1(C)C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[N:5]([C:6]([CH3:12])([CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: CCOC(=O)C(C)(C)NCCCCl
Reactant: O=C=Nc1ccccc1F
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)N(CCCCl)C(=O)Nc1ccccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A solution of ethyl 2-(3-chloropropylamino)isobutyrate (7.5 g) prepared according to Example 3-(1) in toluene (45 mL) was cooled to 0° C. To the solution was added 2-fluoropheyl isocyanate (5 g), and the mixture was stirred overnight at 0° C. to room temperature. Water was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 10.9 g of crude ethyl 2-[3-(2-fluorophenyl)-1-(3-chloropropyl)ureido]isobutyrate.
Reaction SMILES: C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=O)[CH2:31]1.[NH2:39][OH:40]>O1CCCC1>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([NH:39][OH:40])=[O:38])[CH2:31]1
Reactant: NO
Reactant: COCOc1ccc(C2CCCC(C(=O)O)C2)c(OCOC)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCOc1ccc(C2CCCC(C(=O)NO)C2)c(OCOC)c1
Reaction time: 0.5 h

Procedure:
Triethylamine (11 μl) and isobutylchloroformate (10 μl) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanecarboxylic acid in anhydrous tetrahydrofuran (2 ml) at 0° C. under argon. After 30 min, aqueous hydroxylamine solution (0.5 ml, 50 wt %) was added. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound as a solid (26 mg, quant.) and a mixture of diastereoisomers; m/z (ES+) 340 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>C(Cl)Cl>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CN(C)c1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)Cl)cc1

Procedure:
A solution of 4-(dimethylamino)benzoic acid and thionyl chloride in methylene chloride was refluxed 4 h. Volatile solvents were removed in vacuo to yield 1.10 g of 4-(dimethylamino)benzoyl chloride. This material was used in subsequent reactions without purification.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O>[CH2:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:13])=[O:14])[CH3:2]
Reactant: CC(=O)N[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCN[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(C)cc1

Procedure:
Twenty-three grams of trans-N-(2-ACETAMIDOCYCLOHEXYL)-p-TOLUENESULFONAMIDE was added in portions to a stirred suspension of 7 grams of lithium aluminium hydride and 500ml of anhydrous ether. The mixture was stirred and refluxed for 17 hours. The mixture was decomposed by dropwise addition of water and filtered. The filter cake was extracted with a total of 750 ml of boiling ethyl acetate. The organic portions were combined, dried over magnesium sulfate, then evaporated to dryness. The residue was slurried with ether and filtered. On recrystallization from ether there was obtained trans N-(2-ETHYLAMINOCYCLOHEXYL)-p-TOLUENESULFONAMIDE, mp. 112-4°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1.O>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: ClCc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(Oc2ccccc2)cc1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (6.49 g, 30.9 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.23 g, 30.9 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 1-(chloromethyl)-4-(phenyloxy)benzene (8.1 g, 37.0 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was heated under reflux overnight. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) to give ethyl 3-(4-fluorophenyl)-3-oxo-2-((4-(phenyloxy)phenyl)methyl)propionate (7.76 g, crude, 64%).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:29]#[N:30])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][C:22]([F:27])([F:26])[C@@H:21]4[NH2:28])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1.[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:29]([NH2:30])=[O:37])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][C:22]([F:27])([F:26])[C@@H:21]4[NH2:28])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 3-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)pyrazine-2-carbonitrile (41 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (38 mg). MS 430.3 (M+H); UV 202.3, 262.1, 299.7, 358.5 nm; t 0.488 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][O:15][C:14]3=[O:18])=[CH:4][CH:3]=2)=[O:35])=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc2cnn(CCN3CCOC3=O)c2c1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1ccc2cnn(CCN3CCOC3=O)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.4 %

Procedure:
A mixture of 3-[2-(6-Amino-indazol-1-yl)-ethyl]-oxazolidin-2-one (58 mg, 0.24 mmol), 4-benzyloxyphenylacetic acid (68 mg, 0.28 mmol), ethyldimethylpropylcarbodiimide hydrochloride (53 mg, 0.28 mmol), N-hydroxybenzotriazole (37 mg, 0.28 mmol) and N-methyl morpholine (60 mg, 0.56 mmol) in 3 mL of DMF was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel, ethyl acetate/triethylamine, 30/1) to provide the title compound as a pale yellow solid (58 mg, 52%); 1H NMR (300 MHz, DMSO-d6) ppm 3.39 (m, 2H), 3.55 (m, 2H), 3.61 s, 2H0, 4.09 (m, 2H), 4.47 (m, 2H), 5.09 (s, 2H), 6.67 (d, J=8.47, 2H), 7.13 (m, 1H), 7.27 (m, 2H), 7.31–7.45 (m, 5H), 7.65 (m, 1H), 7.97 (m, 1H), 8.13 (s, 1H), 10.30 (s, 1H); MS (DCI/NH3) m/z 471 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([OH:12])[C:4]=1[C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([OH:12])[C:4]=1[C:13](=[N:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:2]
Reactant: N#Cc1c(C(=O)c2ccccc2)n(O)c2ccccc12
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1c(C(=Nc2ccccc2)c2ccccc2)n(O)c2ccccc12

Procedure:
A mixture of 3-cyano-2-benzoyl-1-hydroxy-indole (2.62 g, 10.0 mmole) and aniline (1.0 g, 10.8 mmole) were heated at reflux in toluene (50 ml) under a trap for 16 hours. Concentration in vacuo afforded a solid. Recrystallization from methylcyclohexane provided dark crystals, m.p. 188°-190° C. Analysis (dry 25° C.): Fd(calculated) N, 12.2 (12.4), C, 78.2 (78.3) H, 4.7 (4.5).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:20]([NH-])([CH3:22])[CH3:21].O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:20]([CH3:22])[CH3:21])=[C:7]([OH:12])[CH:6]=1)[CH3:2]
Reactant: CC(C)[NH-]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(OC(C)C)c(O)c1
Yield: 25 %

Procedure:
To a solution of 3,4-dihydroxybenzoic acid ethyl ester (2.0 g, 11 mmol) in acetone (450 l) were added potassium carbonate (2.28 g, 16.5 mmol) and isopropylamide (1.03 ml, 11 mmol), and the resultant mixture was stirred at room temperature for 2 days. The reaction mixture was poured into chilled water and extracted with ethyl acetate under acidic conditions. The organic layer was concentrated, and the residue was chromatographed On a silica gel column to give a mixture (617 mg) of 3-hydroxy-4-isopropyloxybenzoic acid ethyl ester and its position isomer, 4-hydroxy-3-isopropyloxybenzoic acid ethyl ester (6:1). There was observed NOE of protons at 1'-position of the isopropyl group and 5-position. The reaction was effected using this mixture (617 mg) in the same manner as in Reference Example 18, and the resultant product was recrystallized from hexane to give the titled compound (370 mg, yield 12%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15].C1COCC1>CCOCC>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Brc1ccccn1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Sn](C)(C)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of 15.7 mL of 1.6 M n-butyllithium (25.1 mmol) in anhydrous ether (25 mL) was stirred under Ar at −78° C. and to this was added a solution of 2-bromopyridine (3.97 g, 25.1 mmol) in anhydrous ether (12.5 mL). The resulting orange solution was stirred for 2 h, and trimethyltin chloride in THF (26.0 mmol, 26 and, 1.0 M) added over 30 min. The reaction was stirred for 1 h at −78° C. then warmed to room temperature over 1 h, filtered and the filtrate evaporated. Distillation afforded 3.1 g (51%) of the title compound as a colorless liquid which solidified in the receiver flask. B.p. 65° C./2 mm Hg; Literature B.p. 75° C./4 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:21]=O>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[C:18]([F:17])[CH:19]=2)=[C:6]1[CH3:15]
Reactant: O=Cc1ccc(S(=O)(=O)c2ccc(F)cc2)c(F)c1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ccc(S(=O)(=O)c3ccc(F)cc3)c(F)c2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 3-fluoro-4-(4-fluorobenzenesulfonyl)benzaldehyde.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:21]4[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)=[CH:17][NH:18]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31]([N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([C:16]2[C:15]3[C:19](=[CH:20][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[O:11])=[CH:13][CH:14]=3)[NH:18][CH:17]=2)[CH2:22]1)=[O:32]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3c(C4CCCNC4)c[nH]c3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3c(C4CCCN(C(=O)c5cc(F)cc(F)c5)C4)c[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
A mixture of 0.02 g (0.56 mmol) (4-isopropyl-piperazin-1-yl)-(3-piperidin-3-yl-1H-indol-6-yl)-methanone, 0.01 g (0.06 mmol) 3,5-difluorobenzoic acid, 0.02 g (0.06 mmol) TBTU and 0.044 g (0.3 mmol) DIPEA in 0.8 mL DMF was stirred at room temperature for 16 h. The mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient formed from acetonitrile/water/NEt3. Evaporation of the product fractions yielded 16 mg (57%) of the title compounds as off-white foam. MS (m/e): 495.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[C:3]=1[NH2:15].[C:16](OC)(=[O:20])[C:17]([CH3:19])=O>CCCCO>[Cl:1][C:2]1[C:3]2[N:15]=[C:17]([CH3:19])[C:16](=[O:20])[N:8]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](COC)Nc1nccc(Cl)c1N
Reactant: COC(=O)C(C)=O
Solvent: CCCCO
Product: CC[C@H](COC)n1c(=O)c(C)nc2c(Cl)ccnc21
Temperature: 60 °C
Yield: 133.1 %

Procedure:
(R)-4-Chloro-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.24 g, 1.04 mmol) was dissolved in n-BuOH, followed by methyl pyruvate (1.07 g, 10.4 mmol) and the reaction was heated at 60° C. for 5 h, before heating at reflux overnight. The reaction was concentrated in vacuo and purified by column chromatography (20% EtOAc/hex) to yield 0.39 g, 100% of (R)-8-chloro-4-(1-methoxymethylpropyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one: MS (AP) m/z 281.74 [(M+H)+, 100].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:17]=4[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.Cl[C:27]1[N:32]=[C:31]([NH:33][C@@H:34]2[C@@H:39]3[CH2:40][C@@H:36]([CH:37]=[CH:38]3)[C@@H:35]2[C:41]([NH2:43])=[O:42])[C:30]([Cl:44])=[CH:29][N:28]=1>>[Cl:44][C:30]1[C:31]([NH:33][C@@H:34]2[C@@H:39]3[CH2:40][C@@H:36]([CH:37]=[CH:38]3)[C@@H:35]2[C:41]([NH2:43])=[O:42])=[N:32][C:27]([NH:25][C:22]2[CH:23]=[CH:24][C:17]3[CH2:16][CH2:15][CH:14]([N:11]4[CH2:12][CH2:13][CH:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH2:9][CH2:10]4)[CH2:20][CH2:19][C:18]=3[CH:21]=2)=[N:28][CH:29]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: CN1CCN(C2CCN(C3CCc4ccc(N)cc4CC3)CC2)CC1
Product: CN1CCN(C2CCN(C3CCc4ccc(Nc5ncc(Cl)c(N[C@H]6[C@@H](C(N)=O)[C@@H]7C=C[C@H]6C7)n5)cc4CC3)CC2)CC1

Procedure:
The title compound was prepared from 7-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 179 heating at 140° C. Product was isolated as a tan solid (33 mg, 40%). LCMS (m/e) 605 (M+1); 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.38 (dd, 1H, J=7.8 Hz), 7.30 (d, 1H, J=17 Hz), 7.04 (d, 1H, J=8.08 Hz), 6.87 (s, 1H), 6.79 (t, 1H, J=8.08 Hz), 6.33 (m, 1H), 6.30 (m, 1H), 5.59 (s, 1H), 5.43 (s, 1H), 4.37 (t, 1H, J=8.33 Hz), 3.06 (s, 1H), 3.00 (s, 1H), 2.90-2.60 (m, 12H), 2.49-2.38 (m, 5H), 2.27 (s, 4H), 2.19-2.26 (m, 2H), 2.06 (m, 2H), 1.79 (d, 2H, J=11 Hz), 1.63 (d, 1H, J=9.35 Hz), 1.51 (q, 2H, J=11 Hz), 1.38 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]=[CH:9][C:10](Cl)=[O:11])[CH:7]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]=[CH:9][C:10]([N:16]([O:17][CH3:18])[CH3:15])=[O:11])[CH:7]=1
Reactant: O=C(Cl)C=Cc1cc(Br)ccc1F
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)C=Cc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
The unpurified 3-(5-bromo-2-fluoro-phenyl)-acryloyl chloride (1.4 g, 5.0 mmol) prepared in Step 2, N,O-dimethylhydroxylamine hydrochloride (0.52 g, 5.3 mmol), and pyridine (0.9 mL, 11.1 mmol) were added at 0° C. to dichloromethane (10.0 mL). The reaction mixture was stirred at room temperature for 12 hours, quenched with a 1N hydrochloric acid solution, and then extracted with diethyl ether two times. The combined extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was recrystallized from diethyl ether and n-hexane to give 1.3 g of the titled compound as a white solid.