Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:22]([O:34][CH3:35])=[C:23]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:46])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:22]([O:34][CH3:35])=[C:23]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:46])=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)c(OC)c1NS(C)(=O)=O
Yield: 25.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-dimethoxy phenyl)methanesulfonamide (40 mg, 0.05 mmol) was hydrolyzed by lithium hydroxide (23.8 mg, 0.5 mmol), THF/Methanol/water (12/4/4 ml) to afford 7 mg (25.9% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.5 (b, 1H), 8.181-8.177 (d, 1H), 7.525 (s, 1H), 7.356-7.334 (m, 2H), 6.991-6.957 (m, 3H), 6.9-6.85 (m, 1H), 5.363 (s, 2H), 3.930 (s, 3H), 3.499 (s, 3H), 3.184 (s, 1H), 2.231-2.204 (d, 6H). MS: m/z=550.0 (M+1); HPLC: 94.463% in method A.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][CH:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][CH:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][CH:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][C:10]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC2CCCCC2CC1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CC2CCCCC2CC1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Under argon to a solution of 3-tert butoxycarbonylaminodecahydro-2-naphthalenol (0.27 g) in methylene chloride (5 ml was added pyridinium dichromate (572 mg), molecular sieves 3A powder (791 mg) and acetic acid (100 μl ). The reaction mixture was stirred for 50 minutes at room temperature. The black mixture was filtered through a silica gel column (60 g, elution with ethyl acetate:cyclohexane, 1:4) to give, after evaporation of solvents, the title compound as a viscous oil (165 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cn1cncc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cncn5C)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.030 g, 0.076 mmol, 1 eq), EtOH (1.95 mL) and DMF (0.29 mL), p-anisaldehyde (0.011 g, 0.083 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aq NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained as a solid after trituration with diethyl ether (0.009 g, 23%); 1H-NMR (500 Mz, DMSO-d6): δ 2.55-2.62 (m, 4H, piperazine N(CH2)2), 3.54 (s, 2H, NCH2), 3.60-3.66 (m, 4H, piperazine N(CH2)2), 3.68 (s, 3H, imidazole Me), 3.84 (s, 3H, OMe), 6.80 (s, 1H, imidazole 4-H), 7.09 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.57 (s, 1H, imidazole 2-H), 8.13 (d, J=9.0 Hz, 2H, ArH, C6H4), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.35 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.78 min—482/484 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 482.1295, calculated for C22H25BrN7O (M+H)+: 482.1304.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].C(N([CH2:14][CH3:15])CC)C.[C:16]1([O:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[O:22]([C:23]([O:5][CH2:4][CH2:3][N:2]([CH2:6][CH2:7][O:8][C:23]([O:24][C:15]1[CH:14]=[CH:18][CH:17]=[CH:16][CH:21]=1)=[O:22])[CH3:1])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Reactant: CN(CCO)CCO
Solvent: Cc1ccccc1
Product: CN(CCOC(=O)Oc1ccccc1)CCOC(=O)Oc1ccccc1
Temperature: 45 °C

Procedure:
To a 500 ml three-necked round-bottomed flask equipped with an internal thermometer, reflux condenser, mechanical stirrer, addition funnel, and argon inlet are added N-methyldiethanolamine (20.00 g, 0.168 mol), toluene (200 ml), and triethylamine (37.36 g, 0.369 mol). The mixture is treated with a solution of phenylchloroformate (52.56 g, 0.336 mol) dissolved in 50 ml of toluene so as to maintain the reaction temperature at 35°-45 ° C. After addition is complete, the mixture is heated at 45° C. for an additional 1.5 h. The cooled mixture is washed with saturated sodium bicarbonate solution (2×200 ml) and water (200 ml). The organic phase is dried over MgSO4, filtered, and concentrated first by rotary evaporation at 50° C. (water aspirator vacuum) and then at 80° C. (0.02 mmHg) in a Kugelrohr oven to give 3 as a light yellow oil, 55.65 g (92%) that crystallizes on standing.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:17].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[S:29]>>[ClH:17].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]=[C:28]1[N:9]([C@H:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[S:29]1
Reactant: O=S(Cl)Cl
Reactant: C[C@H](NCC(C)(C)O)C1CCCCC1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Product: C[C@@H](C1CCCCC1)N1CC(C)(C)SC1=Nc1cccc(Cl)c1Cl
Product: Cl

Procedure:
(1S)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-((1S)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-3-((1S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2CCN(C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[N:31]1([C:36](=[NH:38])[NH2:37])[CH:35]=[CH:34]C=N1>Cl.O1CCOCC1>[F:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:34][CH2:35][N:31]([C:36](=[NH:38])[NH2:37])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N=C(N)n1cccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(CF)c2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N=C(N)N1CCN(c2cccc(CF)c2)CC1
Temperature: 25 °C

Procedure:
Tert-butyl 4-(3-(fluoromethyl)phenyl)piperazine-1-carboxylate (201.3 mg, mmol) was dissolved in a 4.0 M solution of HCl and dioxane (2 mL) and stirred at room temperature. After 45 min. the reaction mixture was concentrated and re-dissolved in ACN (2 mL). Diisopropylethylamine (22 μL, 1.51 mmol) and 1H-pyrazole-1-carboximidamide (110 mg, 0.75 mmol) were added to the stirring reaction mixture. The next day, the reaction mixture was concentrated to yield a crude oil, which was purified by HPLC using a Phenomenex Luna C-18 (2) column (10 250×21.2 mm, gradient method 0-100% B over 14 min., where B=90% ACN in water using 0.1% TFA as a modifier and A=water using 0.1% TFA as a modifier) with a flow rate of 20 ml/min to isolate 4-(3-(fluoromethyl)phenyl)piperazine-1-carboximidamide as a white solid (42.7 mg, 23% isolated yield over 4 steps). 1H NMR (300 MHz, DMSO-d6): δ 7.58 (br s, 3H), 7.28 (t, 1H, J=7.8 Hz), 7.01 (br s, 1H), 6.98 (br s, 1H), 6.87 (d, 1H, J=7.3 Hz), 5.35 (d, 2H, J=47.9 Hz), 3.58 (dd, 4H, J=5.4, 4.9 Hz), 3.26 (dd, 4H, J=5.4, 4.8 Hz); 13C NMR (75.5 MHz, DMSO-d6): δ 156.1, 150.3, 137.1 (136.8), 129.2, 118.8 (118.7), 115.9, 114.9 (114.8), 84.6 (83.4), 47.2, 44.7; HRMS calcd for C12H17FN4: 237.15100 found 237.1514.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@H:10]3[CH2:12][C@H:11]3NC)[C:4]=2[CH2:3][CH2:2]1.[CH2:15]([N:17]([CH2:20]C)CC)[CH3:16].C(Cl)(=[O:24])C>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@H:10]3[CH2:12][C@H:11]3[CH2:20][NH:17][C:15](=[O:24])[CH3:16])[C:4]=2[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CN[C@@H]1C[C@@H]1c1cccc2c1CCO2
Product: CC(=O)NC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Yield: 50.4 %

Procedure:
The title compound was prepared by the general procedure described in Example 1 using (cis)-2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl methyl amine (0.79 mmol), triethylamine (2.37 mmol) and acetyl chloride (0.95 mmol). Purification by silica gel column chromatography (Hex:EtOAc, 1:1) provided 92 mg of the desired product (50%) as an off-white wax. HPLC purity=93%.
Reaction SMILES: [CH2:1]([OH:3])C.C[O-].[Na+].C(OCC)=O.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=1[OH:19]>C(O)(=O)C.O>[OH:19][C:18]1[CH:17]=[C:16]([CH3:20])[CH:15]=[CH:14][C:13]=1[NH:12][CH:1]=[O:3]
Reactant: CCO
Reactant: Cc1ccc(N)c(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC=O
Solvent: CC(=O)O
Product: Cc1ccc(NC=O)c(O)c1
Reaction time: 1 h
Yield: 32 %

Procedure:
To 20 ml of ethanol, there were added under ice-cooling 4.83 g of sodium methoxide and 18.0 g of ethyl formate. Further, 10.0 g (81.3 mmol) of 6-amino-m-cresol was added thereto under ice-cooling. After putting back to room temperature, the solution was stirred under a nitrogen atmosphere for 1 hour. After the completion of the reaction, the reaction mixture was poured into 200 ml of water. The obtained solution was neutralized with glacial acetic acid, extracted with 300 ml of ethyl acetate, washed with 200 ml of 1N hydrochloric acid and 100 ml of a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, 3.98 g (26.4 mmol) of N-(2-hydroxy-4-methylphenyl)formamide was obtained as a pale brown solid. The yield was 32%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[NH:12][C:11](=S)[NH:10][C:9](=[O:14])[CH:8]=2)[CH2:3][CH2:2]1.BrCC(O)=[O:18].[OH-].[Na+]>CCO.O>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[NH:12][C:11](=[O:18])[NH:10][C:9](=[O:14])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=c1cc(COCC2CC2)[nH]c(=S)[nH]1
Reactant: O=C(O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1cc(COCC2CC2)[nH]c(=O)[nH]1
Temperature: 0 °C
Yield: 36.8 %

Procedure:
6-[(Cyclopropylmethoxy)methyl]-2-sulfanylidene-1,2,3,4-tetrahydropyrimidin-4-one (10.3 g, 48.5 mmol) was added to bromoacetic acid (21.5 g, 155 mmol, 3.2 eq) in EtOH (108 mL) and H2O (441 mL). The reaction mixture was refluxed for 16 h then cooled down to rt and basified to pH˜10 with sodium hydroxide (3 M, aq). The mixture was concentrated in vacuo and hydrochloric acid (aq, 10%) was added. The mixture was cooled to 0° C. The precipitate was isolated by filtration and dried to give the title compound as a solid (3.5 g, 37%).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[N-:9]=[N+:10]=[N-:11].[Na+]>CS(C)=O.C(OCC)C>[N:9]([CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=[N+:10]=[N-:11]
Reactant: ICC1CCOCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Iodomethyl)tetrahydro-2H-pyran (4.76 g, 21.1 mmol) was dissolved in dimethyl sulfoxide (25 mL). Sodium azide (2.70 g, 41.5 mmol) was added and the mixture was stirred at ambient temperature overnight. The resulting slurry was diluted with diethyl ether and washed with water. The organic layer was concentrated under reduced pressure to afford the title compound. The product was used directly in subsequent reactions without characterization.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N:14]=[N:15][NH:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[C:27]#[N:28])#[N:3].[H-].[Na+].[C:31](Cl)(=[O:37])[CH2:32][CH2:33][C:34](Cl)=[O:35].CC[O:41]CC>>[C:31]([CH2:32][CH2:33][C:34]([N:14]([C:5]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:4]=1[C:2]#[N:3])[N:15]=[N:16][C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=1[C:27]#[N:28])=[O:35])([OH:37])=[O:41]
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: CCOCC
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: N#Cc1ccc(C(F)(F)F)cc1N=NN(C(=O)CCC(=O)O)c1cc(C(F)(F)F)ccc1C#N
Reaction time: 12 h

Procedure:
A solution of the sodium salt prepared from 10.0 g. (0.026 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)-triazene and 1.4 g. (0.029 mol.) of sodium hydride in 700 ml. of ether is added dropwise to a solution of 4.65 g. (0.03 mol.) of succinyl chloride in 150 ml. of ether. The reaction mixture is stirred for 12 hours at 25°, filtered and the filtrate is concentrated in vacuo. The residue is washed with hexane, ether is added and the precipitate is removed by filtration. The volume is brought to 500 ml. with ether and a small amount of water is added. The mixture is stirred for 12 hours and the ethereal solution is dried (MgSO4) and concentrated in vacuo to give 3-(3-carboxypropionyl)-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene.
Reaction SMILES: C([O:3][C:4]1[C:13]2[CH:12]=[N:11][C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[N:9][C:8]=2[N:7]=[CH:6][C:5]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.[CH2:26](I)[CH3:27]>>[CH2:26]([N:7]1[C:8]2[N:9]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:11]=[CH:12][C:13]=2[C:4](=[O:3])[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6]1)[CH3:27]
Reactant: CCOC(=O)c1cnc2nc(N3CCN(C)CC3)ncc2c1OCC
Reactant: CCI
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C)CC3)ncc2c1=O

Procedure:
A mixture containing 1.0 g of ethyl 5-ethoxy-2-(4-methyl-1-piperazinyl)pyrido[2,3-d]pyrimidine-6-carboxylate and 5.0 ml of ethyl iodide was heated to reflux for one hour. After ethyl iodide was recovered by distillation, the resulting solid was crystallized from water to give 0.69 g of the product, m.p. 146° - 147°C.
Reaction SMILES: [CH3:1][C@@:2]12[C:17]([CH3:19])([CH3:18])[C@@H:5]([C:6]3[C:7](=[O:16])[N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[NH:9][C:10]=31)[CH2:4][CH2:3]2.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:20]([N:9]1[C:10]2[C@@:2]3([CH3:1])[C:17]([CH3:19])([CH3:18])[C@H:5]([CH2:4][CH2:3]3)[C:6]=2[C:7](=[O:16])[N:8]1[CH2:11][C:12]([F:13])([F:14])[F:15])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(CC(F)(F)F)c(=O)c12
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(CC(F)(F)F)n1Cc1ccccc1
Temperature: 100 °C
Yield: 69.4 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 47; 150 mg, 0.55 mmol), tetrabutylammonium iodide (220 mg, 0.60 mmol) and benzyl bromide (580 μL, 4.9 mmol) in dimethylformamide (2 mL) was heated in a pressure tube in an oil-bath at 100° C. for 20 h. Dichloromethane (75 mL) was added and the solution was washed with water (5×25 mL) and aqueous sodium thiosulfate (25 mL), dried (magnesium sulfate), filtered, evaporated and purified using an ISCO 40 g column, eluting with 20-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated with petroleum ether, triturated with petroleum ether, evaporated, and dried under high vacuum at 70° C. overnight to give (4S,7R)-1-benzyl-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (139 mg, 70%) as a white solid. ES(+)-MS (M+H) 365.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:15][C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][C:21]=3[C:22]=2[N:23]=1.[Cl-].[NH4+:32]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:15][C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:25]([C:28]([NH2:32])=[O:30])=[CH:24][C:21]=3[C:22]=2[N:23]=1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3nncn3-c3ccc(F)cc3F)sc1CCO2
Reactant: [NH4+]
Agent: [Cl-]
Product: NC(=O)c1ccc2c(c1)-c1nc(-c3nncn3-c3ccc(F)cc3F)sc1CCO2

Procedure:
2-[4-(2,4-Difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-9-carboxylic acid and ammonium chloride were reacted in the general amide coupling procedure to give 407. NMR: (CDCl3): 3.32-3.35 (2 H, m), 4.32-4.30 (2 H, m), 6.96-6.99 (1 H, m, Ar), 7.09-7.14 (1 H, m, Ar), 7.48-7.50 (1 H, m, Ar), 7.54-7.58 (1 H, m, Ar), 8.09-8.11 (1 H, m, Ar) and 8.35 (1 H, s, Ar). MS: (ESI+) MH+=425.95
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[CH3:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl-:2].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH2+:16][CH2:23][C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: Cc1ccc(C=O)o1
Reactant: [NH3+]CCOc1ccc2ccccc2c1Cl
Agent: [Cl-]
Product: Cc1ccc(C[NH2+]CCOc2ccc3ccccc3c2Cl)o1
Yield: 70 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]ethanaminium chloride and 5-methylfuran-2-carbaldehyde in 70% yield as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C([Li])(C)(C)C.I[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1>C1COCC1.CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCOC(=O)CCc1ccc(I)cc1
Reactant: CCCCc1ccc(Br)cc1
Agent: [Pd]
Agent: [Li]C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of 3.20 g (15.0 mmol) of 1-bromo-4-butylbenzene (Aldrich Chemical Company #33, 576-2) at -78° C. under argon was added, dropwise over 30 min, 18.0 mL (30.6 mmol, 1.7M in pentane) of t-butyllithium solution. The resulting light yellow solution was warmed to 0° C. and stirred for 1 h. To this solution was added 3.4 g (25 mmol) of thrice-fused zinc chloride in 20 mL of THF. The resulting slurry was stirred for 30 min and then a solution of 2.0 g (6.5 mmol) of 4-iodobenzenepropanoic acid, ethyl ester (Example 43, Part B) and 0.4 g (0.35 mmol) of tetrakis(triphenylphosphine)-palladium(0) in 5 mL of THF was added. The reaction was stirred for 16 h, diluted with ether and washed once with 10% citric acid. The organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (5×20 cm column) eluted with 1:1 hexanes/dichloromethane gave title compound as a colorless oil, 1.79 g , 91% yield.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[OH:15])[CH:10]=[O:11]>C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH2:1][N:2]([CH3:4])[CH3:3])[C:14]=1[OH:15])[CH:10]=[O:11]
Reactant: CNC
Reactant: C=O
Reactant: O=Cc1ccc(O)c(Cl)c1
Solvent: CCO
Product: CN(C)Cc1cc(C=O)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
11.5 g (0.96 mol) of a 40% aqueous dimethylamine solution were added to 7.7 g (0.96 mol) of a 37% aqueous formaldehyde solution in 60 ml of ethanol. Then 10.0 g (0.64 mol) of 3-chloro-4-hydroxybenzaldehyde were added thereto. The reaction mixture was refluxed for 30 minutes and then stirred for 24 hours at room temperature. The precipitated white solid was filtered out and dried.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4]1.[C:19]1([C:25]2[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([NH:17][C:30]([C:27]4[CH:26]=[C:25]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[O:29][N:28]=4)=[O:31])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)c4cc(-c5ccccc5)on4)cc3s2)C1
Reaction time: 3 h

Procedure:
Combine 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.100 g, 0.381 mmol) (Example 1, step 3), dissolved in CH2Cl2 (5.0 mL), with 5-phenyl-isoxazole-3-carboxylic acid (0.079 g, 0.419 mmol), HATU (0.145 g, 0.381 mmol), and DIEA (0.20 mL, 1.14 mmol) in a 40 mL reaction vial and shake the mixture overnight at 40° C. Dilute the mixture with CH2Cl2 (25 mL) and wash with 1.0 M NaOH (25 mL) which results in emulsions forming. Wait 3 h for the emulsions to disappear, separate the layers and dry the organic portion over sodium sulfate. Filter and concentrate in vacuo to yield the compound as a yellow solid. Purify using silica gel chromatography (5% MeOH/CH2Cl2) to afford the title compound as a yellowish-white solid (117 mg, 71%). mass spectrum (m/e): 434.2 [M+1], 432.2 [M−1]. 1H NMR (400 MHz, DMSO-d6): δ10.76 (s, 1H), 8.27 (d, 1H, J=2 Hz), 7.98 (m, 2H), 7.56-7.63 (m, 4H), 7.49 (s, 1H), 7.45 (d, 1H, J=8.8 Hz), 3.73 (t, 1H, J=9.2 Hz), 3.64 (t, 1H, J=9.2 Hz), 3.49 (m, 1H), 3.29 (m, 1H), 2.90 (m, 1H), 2.21 (s, 6H), 2.19 (m, 1H), 1.91 (m, 1H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:27]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH2:35])([CH3:30])([CH3:29])[CH3:28]>CO>[C:27]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH:35][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Solvent: CO
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)NCC(C)(C)C(=O)OC(C)(C)C)nc(C#N)c3c2)cc1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (91 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (90 mg) in MeOH (3 mL) was heated at 100° C. in an oil bath for 48 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (84 mg). LC MS ESI+: 492 (M+1)+.