Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]([CH2:18][CH2:19][F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH2:25]=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:25])[CH2:14][CH2:13]1)[N:8]([CH2:18][CH2:19][F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24]
Reactant: O=C(O)c1cn(CCF)c2nc(N3CCNCC3)c(F)cc2c1=O
Reactant: C=O
Solvent: O=CO
Product: CN1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)CC1
Temperature: 110 °C

Procedure:
A mixture of 6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid (3.0 g), 37% formalin (4 ml) and formic acid (9 ml) is heated at 110° C. for 16 hours with stirring. The reaction mixture is concentrated to dryness under reduced pressure. The residue is dissolved in 10% aqueous ammonia, treated with active charcoal, and filtered. The filtrate is adjusted to pH 8-8.5 with 10% hydrochloric acid. The precipitate is collected by filtration, and recrystallized from acetonitrile to give 2.67 g of 6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid (compound 1), m.p. 224°-226° C.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH2:20](I)[CH3:21]>>[NH2:1][C:2]1[N:7]([CH2:20][CH3:21])[C:6](=[O:8])[C:5]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccncc2)c(=O)[nH]1
Reactant: CCI
Product: CCn1c(N)nc(-c2ccco2)c(-c2ccncc2)c1=O

Procedure:
The title compound was synthesized in a manner similar to that described for Example 3 from 2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone and ethyl iodide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:8][C:7]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=1)=[O:9]
Reactant: CC(=O)c1cc(C)cs1
Reactant: COC(OC)N(C)C
Product: Cc1csc(C(=O)C=CN(C)C)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 1-(4-methyl-2-thienyl)ethanone (70.8 mmol) and N,N-dimethylformamide dimethyl acetal (105.1 mmol) was refluxed overnight and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and dried in vacuo to afford 13.8 g (100% yield) of 3-(dimethylamino)-1-(4-methyl-2-thienyl)prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C(NCC)C>CO>[N+:17]([CH2:20][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])([O-:19])=[O:18]
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: C[N+](=O)[O-]
Solvent: CCNCC
Solvent: CO
Product: O=C(CC(C[N+](=O)[O-])c1ccccc1)c1ccccc1
Yield: 96.3 %

Procedure:
In a 1 L flask, 94.7 g (0.455 mol) of benzylideneacetophenone were dissolved in 600 g of methanol, admixed with 138.9 g (2.275 mol) of nitromethane and 166.4 g (2.275 mol) of diethylamine and refluxed for 16 h. The solvent was half distilled off in vacuo and the precipitated solid was separated off and dried to constant weight in vacuo to obtain 118 g (438 mmol) of 4-nitro-1,3-diphenylbutan-1-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[N:33]=[C:34]=[O:35]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[NH:33][C:34]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:35]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc([N+](=O)[O-])cc4Cl)cc3)c2cc1OC
Yield: 99 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (104 mg) was dissolved in toluene (10 ml) with heat, 2-chloro-4-nitrophenyl isocyanate (150 mg) was added, and the admixture was refluxed with heat for 10 minutes. The separated crystals were filtered and then washed with toluene to obtain 172 mg of the title compound (yield: 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH3:22].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.Cl>[CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=1[C:11]([N:21]([CH3:22])[CH3:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)cc(F)c1OCc1ccccc1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(Br)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Benzyloxy-5-bromo-3-fluoro-benzoic acid (product from step 2) (0.2 g, 0.615 mmol) is dissolved in THF (10 ml) and treated with 2M dimethylamine in THF (0.308 ml), N-methylmorpholine (0.270 ml, 2.46 mmol) and HATU (0.234 g, 0.615 mmol) and stirred at room temperature overnight. The reaction mixture is diluted with 2M HCl and extracted with EtOAc (2×), the organic portions are combined washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting crude residue is dry loaded onto silica and purification by flash chromatography eluting with EtOAc affords the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[C:5]([Cl:25])=[CH:4][N:3]=1.Cl.[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:25][C:5]1[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)=[N:7][C:2]([NH:33][C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(Cl)ncc2Cl)C2(CCCC2)C1
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2ncc(Cl)c(NC3CN(C(=O)OC(C)(C)C)CC34CCCC4)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of tert-butyl 4-((2,5-dichloropyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (830 mg, 2.15 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (344.74 mg, 2.58 mmol) in n-BuOH (8 mL) was added DIPEA (833.60 mg, 6.45 mmol) and the reaction mixture was stirred at 150° C. overnight. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the product as a white solid (800 mg, 83%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[N:13]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[CH:11][CH:10]=1>C(O)(=O)C>[C:5]([NH:8][C:9]1[N:13]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:21]([F:22])([F:24])[F:23])=[CH:16][C:15]=2[Cl:25])[N:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccnn1-c1c(F)cc(C(F)(F)F)cc1Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccnn1-c1c(F)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 9 h
Yield: 76.9 %

Procedure:
3.7 ml (0.038 mol) of acetic anhydride are added to 100 g (0.036 mol) of 5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole in 60 ml of glacial acetic acid, and the mixture is stirred at room temperature for 9 hours. For working-up, the reaction mixture is added dropwise to 300 ml of ice-water, and the precipitate formed is filtered off, washed with water and dried in vacuo at 50° C. 8.9 g (77% of theory) of 5-acetamido-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole of melting point 144°-146° C. are obtained.
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)[OH:6].N[C@@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14]>>[C:16]([OH:18])(=[O:17])[C@@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[OH:6]
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)C[C@@H](O)C(=O)O
Reaction time: 0.25 h

Procedure:
While heating and stirring 100 ml of aqueous solution of 14 g of sodium nitrite at 90° C., 400 ml aqueous solution of 0.5N sulfuric acid of 25 g of D-leucine was added over 45 minutes. After dripping, the solution was stirred for 15 minutes until foams were no longer generated. The reaction solution was concentrated to 200 ml in vacuo, and the obtained residue was extracted with diethyl ether. The diethyl ether layer was washed one with 1N hydrochloric acid, and twice with saturated brine sequentially, and dried over sodium sulfate anhydride, and concentrated in vacuo. The obtained oily residue was left over, crystallized, and the captioned compound was obtained. Yield: 14.50 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[N:3]=1.[C:21](=[O:24])([O-])[O-:22].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:22]1[C:9]2[CH:10]=[CH:11][C:12]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]4)[N:3]=3)=[CH:13][C:8]=2[O:24][CH2:21]1
Reactant: O=C([O-])[O-]
Reactant: OC1CCN(c2nc(Cl)cc(-c3ccccc3)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC1CCN(c2nc(-c3ccccc3)cc(-c3ccc4c(c3)OCO4)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of compound benzo[1,3]dioxo-5-yl boronic acid (0.14 g, 83 mmol), and compound 1-(4-chloro-6-phenyl-pyrimidin-2-yl)-piperidin-4-ol (90.2 g, 69 mmol), (PPh3)4Pd (31 mg, 0.03 mmol) and sodium carbonate (0.73 g, 69 mmol) in dimethylformamide (5 mL) was stirred for 1 hour at 25° C. and then for 12 hours at 80° C. under nitrogen atmosphere. The mixture was cooled to temperature in the range of 20-40° C., diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were collected, combined, washed with water (10 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum. The residue thus obtained was purified by column chromatography using ethyl acetate-petroleum ether to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[C:14]([Cl:15])=[N:13][S:12][N:11]=2)=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@H:24]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:16]([O:20][C:21]([NH:23][C@H:24]([CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([NH:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:10]1[C:14]([Cl:15])=[N:13][S:12][N:11]=1)=[O:30])=[O:26])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: NCc1cc(Cl)ccc1-c1nsnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1nsnc1Cl)C1CCCCC1

Procedure:
To a stirred solution of 1-[5-chloro-2-(4-chloro-1,2,5-thiadiazol-3-yl)phenyl]methanamine (28.1 mg, 0.11 mmol), 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-proline (prepared by standard peptide coupling protocols, 38.3 mg, 0.11 mmol) and HOAt (19.1 mg, 0.14 mmol) in DMF (1.0 mL) was added EDC (26.9 g, 0.14 mmol). After 16 h the mixture was partitioned between EtOAc and water. The organic phase was washed with brine dried (Na2SO4) and reduced in vacuo. The residue was purified by HPLC (C18 eluting with an acetonitrile/water/0.1% TFA gradient). 1-{(2R)-2-[(tert-Butoxycarbonyl)amino]-2-cyclohexylethanoyl}-N-[5-chloro-2-(4-chloro-1,2,5-thiadiazol-3-yl)benzyl]-L-prolinamide was obtained as a solid. LCMS m/z=596.5.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH:6]([C:8]1[N:17]=[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:29])[CH:14]=2)[N:9]=1)=O>C(O)C>[OH:3][N:2]=[CH:6][C:8]1[N:17]=[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:29])[CH:14]=2)[N:9]=1
Reactant: O=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
0.60 g of hydroxylamine hydrochloride and 3.0 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 1.00 g (2.93 mmol) of 2-formyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 30 ml of ethanol. The obtained mixture was stirred at 60° C. for 30 minutes and cooled by allowing to stand. The crystal thus precipitated was recovered by filtration, washed with ethanol and n-hexane and air-dried to give 1.00 g of the title compound as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=1[CH:5]=CC=O.[O-:17][Mn](=O)(=O)=O.[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=1[CH:5]=[O:17]
Reactant: COc1cc(OC)c(OC)cc1C=CC=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)c(OC)cc1C=O
Reaction time: 24 h
Yield: 45.3 %

Procedure:
A solution of the 2,4,5-Trimethoxycinnamaldehyde (0.5 g) was treated with KMnO4 (0.5 g) in dry acetone (20 ml). The reaction mixture was left at room temperature for 24 hr, manganese dioxide was filtered off and the solvent was removed. The residue was dissolved in ethyl acetate and washed carefully with 10% NaHCO3, brine, and dried over anhydrous Na2SO4. Evaporation of the solvent afforded a crude solid, which was further recrystallised from water to afford 0.2 g 2,4,5-trimethoxybenzaldehyde as a colorless solid, mp 114° C. (lit. mp 114° C.); IR (film) νmax 1662 (carbonyl group), 1620, 1518, 1481, 1419, 1361, 1300, 1278, 1222, 1199, 1138, 1025, 865 cm−1; 1H NMR δ 10.32 (1H, s, CHO), 7.33 (1H, s, 6H), 6.50 (1H, s, 3H), 3.98 (3H, s, 2-OCH3), 3.93 ((3H, s, 4-OCH3), 3.88 (3H, s, 5-OCH3); 13C NMR δ 187.96 (CHO), 158.60 (C-2), 155.76 (C-4), 143.56 (C-5), 117.35 (C-1), 109.03 (C-6), 56.19 (2-OCH3, 4-OCH3 and 5-OCH3); EIMS m/z 196 [M]+ (100), 181 (49), 150 (32), 125 (33), 110 (23), 69 (37).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C=O.[C:37]([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:37])[CH2:16][CH2:17][CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(NCCCNCCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Agent: C=O
Agent: [Na+]
Product: COc1ccc(NCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-3-(3,4-dimethoxyphenylamino)-propylamine, paraformaldehyde and sodium cyanoborohydride analogously to Example 5.
Reaction SMILES: [C:1]([C:5]1[C:12]2[S:11][C:10]([NH2:13])=[N:9][C:8]=2[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]([C:5]1[C:12]2[S:11][C:10]([NH:13][C:25]([C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)=[O:26])=[N:9][C:8]=2[NH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1n[nH]c2nc(N)sc12
Reactant: O=C(Cl)c1ccco1
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)c1n[nH]c2nc(NC(=O)c3ccco3)sc12
Temperature: 70 °C
Reaction time: 23 h
Yield: 81 %

Procedure:
To a stirring solution of 3-tert-Butyl-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.153 mmol) and pyridine (74 μL, 0.92 mmol), or alternatively PS-DMAP (Argonaut resin, 6 equiv.), in THF (0.75 mL) was added furan-2-carbonyl chloride (75 μL, 0.76 mmol). The reaction mixture was stirred at 70° C. for 23 h, then cooled to room temperature and treated with THF (1 mL) and PS-trisamine (Argonaut resin, 20 equiv.) for 2 h. The resin was filtered, washed with DMF and the solvent was evaporated. The residue was treated with MeOH (1 mL) and a 4N aqueous solution of NaOH (0.25 mL) and the solution was stirred at room temperature for 2 h. The reaction mixture was neutralized to pH 7 with a 1N aqueous solution of HCl and extracted with ethyl acetate (3×). Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 36 mg (82%) of furan-2-carboxylic acid (3-tert-butyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-amide as an off-white solid. 1H-NMR (d6-DMSO) δ: 12.8 (broad s, 1H, NH), 12.7 (broad s, 1H, NH), 8.03 (d, 1H), 7.69 (broad s, 1H), 6.74 (dd, 1H), 1.36 (s, 9H); HPLC/MS m/z: 291 [MH]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:23])[C:9]1[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[O:21][CH3:22].Br[CH2:25][CH2:26][O:27][CH2:28][CH2:29]Br>>[CH3:22][O:21][C:10]1[CH:11]=[C:12]([C:17]([F:19])([F:20])[F:18])[CH:13]=[C:14]([S:15][CH3:16])[C:9]=1[C:8]([NH:7][CH:3]1[CH2:4][CH2:5][CH2:6][CH:2]1[N:1]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Reactant: BrCCOCCBr
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCOCC1

Procedure:
The title compound, white solid, MS: m/e=419.1 [(M+H)+], was prepared in accordance with the general method of example 10 from N-((1RS, 2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and bis(2-bromoethyl)ether.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C:6]1=O)=[O:4].C(O)(=O)C.Cl(O)(=O)(=O)=O>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1Cc2ccc(OC)cc2C1=O
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C1Cc2ccc(OC)cc2C1
Reaction time: 12 h
Yield: 64.6 %

Procedure:
Combine in a Parr shaker 6-Methoxy-1-oxo-indan-2-carboxylic acid methyl ester (3.14 g, 14.25 mmol), added acetic acid (150 mL), perchloric acid (0.8 mL) and 5% Pd—C (0.14 mmol). After the reaction has been on the parr shaker under 40 atm of H2 pressure at room temperature for 12 hours, filter the reaction mixture through a pad of Celite using ethyl acetate eluent. Then add the filtrate to a separatory funnel and wash with water then brine, and dry the organic layer over Na2SO4. After concentrating under reduced pressure, flash Chromatograph using 8:1 Hexanes:Ethyl acetate to afford 1.9 g, 9.21 mmol (65% yield) of the title compound as a clear oil: 1H NMR (500 MHz, CDCl3); 3.2-3.4 (5H, m), 3.7 (3H, s), 3.8 (3H, s), 6.7-6.8 (2H, m), 7.1-7.2 (1H, m); TLC 1:1 Hexanes:Ethyl acetate Rf:=0.6.
Reaction SMILES: [C:1]12([C:11]3[O:15][C:14]([C:16](O)=[O:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:19]([O:21][C:22](=[O:32])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:32])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:16]([C:14]2[O:15][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:12][CH:13]=2)=[O:17])[CH:26]=1)[CH3:20]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(C23CC4CC(CC(C4)C2)C3)o1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(C34CC5CC(CC(C5)C3)C4)o2)c1

Procedure:
5-Adamantan-1-yl-furan-2-carboxylic acid (50 mg, 0.20 mmol) was coupled to aniline (60) (43 mg, 0.22 mmol) using Method D to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][O:11][C:12]2[O:13][C:14]3[C:19]([C:20](=[O:23])[C:21]=2[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH3:22][C:21]1[C:20](=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12]=1[O:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:25][CH:24]=1
Reactant: Cc1c(OCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(COc3oc4ccccc4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
To a solution 2-[4-(4-hydroxy-butyl)-benzyloxy]-3-methyl-chromen-4-one (101 mg, 0.30 mmol) dissolved in anhydrous dichloromethane (3.0 mL) was added TsCl (68 mg, 0.36 mmol), DMAP (55 mg, 0.45 mmol) and TEA (0.050 mL, 0.36 mmol). The reaction mixture continued stirring at room temperature. After 20 h, the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate) to yield toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-chromen-2-yloxymethyl)-phenyl]-butyl ester (75.2 mg, 0.15 mmol) in moderate yield (51%). 1H (CDCl3, 600 MHz): δ 8.21 (1H, dd, J=8.2,1.5 Hz), 7.77 (2H, d, J=8.3 Hz). 7.60 (1H, m), 7.33 (2H, d, J=8.0 Hz), 7.36 (2H, d, J=8.0 Hz), 7.39 (2H, d, J=8.2 Hz), 7.33 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=7.9 Hz), 5.43 (2H, s), 4.04 (2H, t, J=5.9 Hz), 2.59 (2H, t, J=7.3 Hz), 2.44 (3H, s), 1.99 (3H, s), 1.68 (4H, m);); 13C (CDCl3, 150 MHz): δ 178.2, 161.8, 152.2, 144.2, 141.9, 132.7, 132.2, 131.9, 129.3, 128.3, 127.7, 127.4, 125.6, 127.7, 122.1, 116.1, 70.1, 69.8, 34.3, 27.9, 26.5, 21.1, 6.7. HRMS calcd for C28H28O6S: 545.1498. found. 515.1493.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32]C2C=CC=CC=2)=[CH:28][CH:27]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[O:2])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: COc1ccc(Nc2ccccc2)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: COc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 49.6 %

Procedure:
In a similar manner to Example 51, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 4-methoxyphenylaniline (22.9 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-methoxyphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (19.7 mg).