Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH:7]=[N:6]1.[Cl-].[NH4+]>[Fe].C(O)C.O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[CH:7]=[N:6]1
Reactant: CN(C)CCn1ncc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)CCn1ncc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A mixture of dimethyl-[2-(6-nitro-indazol-1-yl)-ethyl]-amine (1 g, 4.3 mmol), iron powder (1.9 g, 34 mmol), and ammonium chloride (120 mg, 2.2 mmol) in a 4:1 Ethanol/H2O solution (20 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 10 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4), and the filtrate concentrated under reduced pressure to provide the title compound (0.8 g, 92%). 1H NMR (300 MHz, DMSO-d6) ppm 2.17 (s, 6H), 2.63(t, J=6.44, 2H), 4.23 (t, J=6.44, 2H), 5.28(s, 2H), 6.50 (m, 2H), 7.35 (m, 1H), 7.69 (m, 1H); MS (DCI/NH3) m/z 205 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH:7]=O)=[C:5]([OH:13])[CH:4]=1.[OH-].[K+].[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21](=[O:24])[CH2:22]Br>C(O)C.O>[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21]([C:22]1[O:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[CH:9][C:6]=2[CH:7]=1)=[O:24]
Reactant: COC(=O)CCC(=O)CBr
Reactant: COc1cc(O)c(C=O)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)CCC(=O)c1cc2cc(OC)c(OC)cc2o1
Reaction time: 0.33 h
Yield: 32.1 %

Procedure:
To a stirred suspension of 4,5-dimethoxy-2-hydroxy-benzaldehyde (9.3 g) in dry ethanol (90 ml) under nitrogen was added slowly a solution of potassium hydroxide (3.14 g) in dry ethanol (60 ml). The resulting solution was stirred for 20 minutes, then 5-bromo-4-oxo-pentanoic acid methyl ester (10.65 g) was added slowly. The mixture was stirred for 24 hours, then diluted slowly with water (900 ml). The precipitated solid was filtered off, washed with water, dried under vacuum and crystallized from acetone-ether to give 4-(5,6-dimethoxy-benzo[b]furan-2-yl)-4-oxo-butanoic acid methyl ester (4.78 g).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][C:6]=1[NH:7][C:8](=[O:10])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:37]1([C:43]#[CH:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>[Pd].C(O)C.[Cu]I>[C:37]1([C:43]#[C:44][C:2]2[CH:3]=[N:4][NH:5][C:6]=2[NH:7][C:8](=[O:10])[CH3:9])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Nc1[nH]ncc1I
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)Nc1[nH]ncc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Nitrogen was bubbled through a suspension of N-(4-iodo-1H-pyrazol-5-yl)acetamide (30 g, 120 mmol), 10% palladium on carbon (50% water, 7.4 g, 3 mmol), copper(I) iodide (1.14 g, 6 mmol), triphenylphosphine (6.3 g, 24 mmol) and triethylamine (50 mL, 360 mmol) in ethanol (600 mL) for 20 min. Phenyl acetylene was added and nitrogen bubbled through the mixture for a further 25 min. The reaction mixture was then heated and stirred under reflux conditions in an atmosphere of nitrogen for 3 d and cooled to room temperature. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, iso-hexanes/ethyl acetate 9:1 to 0:1) yielding the title compound as a solid (17.6 g).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:25]([NH2:27])=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=1)=[O:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:25]([NH2:27])=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:22])[CH3:23])[CH:16]=1)=[O:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)N[C@@H](Cc1cccc(C(C)(C)C)c1)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cccc(C[C@H](NC(=O)[C@@H](N)CC2CCCCC2)C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 322 mg (0.681 mmol) of Boc-Cha-Phe(3-tBu)-NH2 in 2 ml of methylene chloride, 1 ml of TFA was added and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to give a TFA salt of Cha-Phe(3-tBu)-NH2; to a solution of the TFA salt in 2 ml of DMF, 0.1 ml of TEA, 343 mg (0.817 mmol) of Z-Phe-ONp and 125 mg (1.02 mmol) of DMAP were added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO3, then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol=10:1) to give Z-Phe-Cha-Phe(3-tBu)-NH2 in the amount of 192 mg (43%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[Ca+2].[OH-].Br[CH:13]([CH3:22])[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:15]>CS(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH:13]([CH3:22])[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:15])=[CH:4][CH:3]=1
Reactant: CCCCCOC(=O)C(C)Br
Reactant: Oc1ccc(O)cc1
Agent: [Ca+2]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
264 g (2.4 moles) of hydroquinone were dissolved in 800 ml of anhydrous dimethylsulfoxide, and 89 g (1.2 moles) of calcium hydroxide were added. The mixture was stirred for 30 minutes at room temperature, after which it was cooled to 10° C. 268 g (1.2 moles) of n-pentyl 2-bromopropionate were added dropwise in the course of 3 hours, while maintaining this temperature. Thereafter, the mixture was left to warm up to room temperature, and stirred for 20 hours at this temperature. Finally, the mixture was worked up as described in Example 1. 214 g (0.85 mole) of n-pentyl 2-(4-hydroxyphenoxy)-propionate were obtained. Yield: 70.8%; bp.=149°-150° C./0.2 mbar. ##STR6##
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][C:6]1[CH:7]=[C:8]2[C:15](=[O:16])[O:14][C:12](=[O:13])[C:9]2=[N:10][CH:11]=1>C(Cl)Cl>[CH:1]([NH:4][C:12]([C:9]1[C:8]([C:15]([OH:16])=[O:14])=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:13])([CH3:3])[CH3:2]
Reactant: Cc1cnc2c(c1)C(=O)OC2=O
Reactant: CC(C)N
Solvent: ClCCl
Product: Cc1cnc(C(=O)NC(C)C)c(C(=O)O)c1
Yield: 91.5 %

Procedure:
3.25 g of isopropylamine are added to 8.1 g of 5-methylpyridine-2,3-dicarboxylic anhydride in 50 ml of methylene chloride at from 20° to 30° C. while stirring, and the stirred mixture is refluxed for 3 hours. The reaction mixture is evaporated down under reduced pressure and the residue is stirred in a 1:1:1 mixture of ether, methyl tert-butyl ether and petroleum ether. Filtration under suction and drying give 10.1 g of the title compound as colorless crystals of melting point 95°-105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)[C:6]2=[O:23]>CO.O1CCCC1.[Pd]>[NH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][CH:7]1[C:6](=[O:23])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:9][CH2:8]1
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)CO2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C(Cc1cccc(N)c1)CO2
Temperature: 25 °C
Yield: 107 %

Procedure:
A mixture of 10.20 g (32.8 mmol) of the product of Example 1 and 2 g of 10% Pd/C in 200 mL CH3OH and 200 mL tetrahydrofuran was shaken on a Parr (trademark) hydrogenation apparatus at 25 psi H2 at room temperature. After 30 minutes the reaction mixture was filtered through diatomaceous earth (Celite [trademark]), and the filtrate concentrated in vacuo to yield 9.94 g of a yellow solid. Silica gel chromatography eluting with 5% ethyl acetate-CH2Cl2 afforded 8.53 g of a yellow solid (92%). A small sample was recrystallized from ethyl acetate-hexane to obtain analytical data. M.p. 137°-139° C.; MS: 283M+, 107 Base; 1H NMR (AC 300, CDCl3): δ4.3 (1H, m); 4.15 (1H, m), 3.82 (3H, s); 3.7 (1H, m); 3.67 (1H, m); 2.9 (1H, m); 2.6 (1H, m); IR: 3430, 3250, 1660 cm-1. Analysis: calculated: C. 72.07, H 6.05, N 4.94%; found: C: 71.69, H 6.01, N 4.96%.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([N:34]3[CH2:45][CH2:44][C:43]4[C:42]5[CH2:41][C:40]([CH3:47])([CH3:46])[CH2:39][C:38]=5[S:37][C:36]=4[C:35]3=[O:48])[C:31]=2[CH:32]=[O:33])=[CH:3]1.[BH4-].[Na+].[CH3:51][OH:52]>>[OH:33][CH2:32][C:31]1([CH:51]=[O:52])[C:30]([N:34]2[CH2:45][CH2:44][C:43]3[C:42]4[CH2:41][C:40]([CH3:46])([CH3:47])[CH2:39][C:38]=4[S:37][C:36]=3[C:35]2=[O:48])=[CH:29][N:28]=[CH:27][CH:26]1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:23][O:24][CH2:25]4)[CH2:20][CH2:21]3)=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: CO
Reactant: Cn1cc(-c2cncc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Product: Cn1cc(C2C=NC=C(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)C2(C=O)CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 106j (130 mg, 0.20 mmol) in methanol (5 mL) at 0° C. was added sodium borohydride (22 mg, 0.6 mmol) and stirred for 30 minutes. Then the reaction mixture was quenched with water (1.0 mL) and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 106 (60 mg, 45%) as a yellow solid. LCMS: [M+H]+ 668. 1H NMR (500 MHz, DMSO) δ 8.58 (d, J=2.0, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 7.87 (d, J=2.5, 1H), 7.38-7.36 (m, 2H), 7.24-7.22 (m, 1H), 5.15 (t, J=5.0, 1H), 4.56-4.42 (m, 6H), 4.08-4.04 (m, 2H), 3.60 (s, 3H), 3.43-3.42 (m, 1H), 3.07-2.94 (m, 6H), 2.55-2.53 (m, 4H), 2.39-2.38 (m, 4H), 1.23 (s, 6H)
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]#[N:18])=[CH:11][C:10]=1[CH3:19]>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:16][C:17]#[N:18])[C:5](=[O:7])[CH3:6])=[CH:11][C:10]=1[CH3:19]
Reactant: Cc1cc(NCC#N)ccc1Br
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(CC#N)c1ccc(Br)c(C)c1
Temperature: 115 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Acetic anhydride (4.99 ml) was added to (4-bromo-3-methyl-phenylamino)-acetonitrile (594 mg, 2.64 mmol), and the mixture was heated with stirring at 115° C. for one hour. The reaction solution was cooled and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give N-(4-bromo-3-methyl-phenyl)-N-cyanomethyl-acetamide (697 mg, 99%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:28]2[N:29]=[CH:30][CH:31]=[N:27]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: c1c[nH]nn1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-n2nccn2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 14.9 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 1H-1,2,3-triazole (197 mg, 2.84 mmol) and potassium carbonate (47 mg, 0.34 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 20:60:20, 34 mg, 15%) which was obtained as a white solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCCN(C)C1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 2.47 g (6.0 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]-dihydrofuran-2-(3H)-one dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are deprotonated at -70° C. with 11.73 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (75 min) with 0.713 ml (6.0 mmol) of benzyl bromide in 3 ml of THF. Column chromatography (SiO2, hexane/ethyl acetate 4:1→2:1) and crystallisation from ether/hexane yields the pure title compound: TLC Rf (D)=0.36.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[C:13]([N:20]1[CH2:25][CH2:24][N:23]2[CH2:26][C@H:27]([CH2:30]OS(C)(=O)=O)[CH2:28][CH2:29][C@H:22]2[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl>CN(C=O)C.O>[C:13]([N:20]1[CH2:25][CH2:24][N:23]2[CH2:26][C@H:27]([CH2:30][N:7]3[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[CH2:28][CH2:29][C@H:22]2[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](COS(C)(=O)=O)CC[C@H]2C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2C[C@H](Cn3ccc4cc(F)ccc43)CC[C@H]2C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 35.9 %

Procedure:
A solution of 8.41 g (62 mmol) of 5-fluoroindole in 250 mL of DMF was treated with 2.46 g (62 mmol) of sodium hydride (60% oil dispersion) and the mixture stirred at 50° C. for 1.5 h. Heating was stopped temporarily, 7.73 g (22.2 mmol) of (7R,9aS)-2-BOC-7-(methanesulfonyloxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 250 mL of DMF was added, and the mixture stirred at 100° C. for 2 h. The mixture was cooled to room temperature, diluted with water, acidified to pH 2 with 6M hydrochloric acid, and washed with ethyl acetate. The aqueous phase was basified to pH 12 with conc. ammonium hydroxide and extracted with ethyl acetate (3×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate gave 3.09 g (36%) of (7R,9aS)-2-BOC-7-(5-fluoroindol-1-yl)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: Cl.[CH2:2]([S:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH3:3].[Na].C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C(O)(=O)C>C(O)C>[O:17]=[C:18]1[NH:9][C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH2:2][CH3:3])=[N:8][CH:25]=[C:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCSc1ccccc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(-c2ccccc2SCC)[nH]c1=O
Temperature: 0 °C
Yield: 67 %

Procedure:
2-Ethylthiobenzamidine hydrochloride (2.12 g., 10.0 mmoles) was added to a cooled (ice-water) solution of sodium (0.46 g., 20 mg.-atoms) in ethanol (12 ml.). To this mixture was added a solution of diethyl ethoxymethylenemalonate (2.16 g., 10.0 mmoles) in ethanol (4 ml.). The mixture was heated under reflux for 3.5 hours. The cooled mixture was poured into ice-water (400 ml.) and acidified to pH 6 with glacial acetic acid. The precipitate was collected and recrystallized from acetonitrile to give the title compound (2.04 g., 64.6%), m.p. 117°-120°.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH3:27])[CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:5]=2[N:4]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[F:34][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH3:27])[CH:21]3[CH2:26][CH2:25][N:24]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(C)C2CCNCC2)n1
Reactant: CS(=O)(=O)Cl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(C)C2CCN(S(C)(=O)=O)CC2)n1
Yield: 56 %

Procedure:
Reaction of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-6-(4-morpholinyl)-N-(4-piperidinyl)-1,3,5-triazin-2-amine from the previous step with methanesulphonyl chloride as in Example 4 gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine in 56% yield: mp (CH2Cl2/MeOH) 190-192° C.; 1H NMR (DMSO-d6) (rotamers) δ 7.97 and 7.89 (2d, J=8.3, 8.5 Hz, 1H), 7.69 and 7.74 (2t, JHF=52.9 Hz, 1H), 7.46-7.39 (m, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.69-4.61 (m, 1H), 3.98 (s, 3H), 3.80-3.69 (m, 10H), 3.09 and 2.95 (2s, 3H), 2.93-2.92 (2s, 3H), 2.92-2.78 (m, 2H), 1.93-1.67 (m, 4H); Anal. Calcd. for C23H30F2N8O4S: C, 50.0, H, 5.5, N, 20.3. Found: C, 49.5, H, 5.3; N, 20.0%.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:13]([O-])=O)[CH:5]=1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:13][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: CC(C)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(C(=O)O)c(N)c1
Yield: 98 %

Procedure:
The product of Example 91C (0.697 g, 3.332 mmol) was hydrogenated in methanol (30 mL) with 10% palladium-on-carbon (70 mg) at 1 atmosphere hydrogen pressure (balloon) for 2 hours. The reaction was filtered through a 0.45 micron PTFE membrane and the catalyst thoroughly washed with methanol. The filtrate was concentrated by rotary evaporation to give the title compound (0.585 g, 3.264 mmol, 98%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.15 (d, J=6.62 Hz, 6 H) 2.61-2.92 (m, 1 H) 6.41 (dd, J=8.46, 1.47 Hz, 1 H) 6.58 (d, J=1.84 Hz, 1 H) 7.60 (d, J=8.46 Hz, 1 H) 8.46 (br s, 2 H); MS (ESI+) m/z 180 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH3:42])=[C:10]([CH:41]=2)[C@H:11]([C:29]2[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][C:30]=2[CH3:40])[O:12]C(=O)[C@H](C2C=CC3C(=CC=C(OC)C=3)C=2)C)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO>[OH:12][C@@H:11]([C:29]1[C:30]([CH3:40])=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][C:38]=1[CH3:39])[C:10]1[CH:41]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=[CH:8][C:9]=1[CH3:42]
Reactant: COC(=O)c1cc(C)c([C@H](OC(=O)[C@@H](C)c2ccc3cc(OC)ccc3c2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-n2ccnc2)cc1[C@@H](O)c1c(C)cc(C(=O)O)cc1C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
Methyl (R)-4-[5-(1-imidazolyl)-α-{(S)-2-(6-methoxy-2-naphthyl)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate (35 g) obtained in Example 9 was suspended in methanol (280 ml) and an aqueous solution (70 ml) containing sodium hydroxide (6.2 g) was added, which was followed by sting at 60° C. for 2 hours. The reaction mixture was concentrated and to the residue were added dimethylformamide (210 ml) and water (210 ml), which was followed by neutralization with glacial acetic acid (17.5 ml). The precipitated crystals were collected by filtration, washed with water and acetone, and recrystallized from dimethylformamide to give 17.8 g of (R)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, melting point 286-288° C. (decomposition), optical rotation [α]D21 +260.5° (c=1.0, dimethylformamide).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)=[CH:4][C:3]=1[N+:21]([O-])=O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH2:21])[CH:4]=2)[CH2:13][CH2:12]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)c([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(N)c2)CC1
Reaction time: 72 h
Yield: 80.6 %

Procedure:
A mixture of tert-butyl 4-(4-fluoro-3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (2.35 g, 8.85 mmol) and 10% Pd/C (400 mg) in ethyl acetate (40.0 mL) and methanol (10.0 mL) was hydrogenated at room temperature for 72 hours using hydrogen bomb (200 psi). The reaction mixture was filtered through Celite and the Celite was washed with EtOAc/MeOH (1:1, 3×50 mL). The filtrate was concentrated in vacuo to afford tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidinecarboxylate (2.10 g, 98.0%): 1H NMR (400 MHz, CDCl3) δ 6.96-6.76 (m, 1H), 6.67-6.54 (m, 1H), 6.54-6.40 (m, 1H), 4.38-4.09 (br, 2H), 4.09-3.58 (br, 2H), 2.87-2.62 (m, 2H), 2.60-2.39 (m, 1H), 1.85-1.65 (m, 2H), 1.64-1.40 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:22][C:23](=[O:33])[C:24]4[C:29]([CH:30]=3)=[C:28]([C:31]#[CH:32])[CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[C:31]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:29]=1[CH:30]=[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:16][CH:17]=1)[NH:22][C:23]2=[O:33])#[CH:32]
Reactant: C#Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C#Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCNCC4)cc3)cc12
Yield: 34.3 %

Procedure:
4-[4-(5-Ethynyl-1-oxo-1,2-dihydroisoquinolin-3-yl)benzyl]piperazine-1-carboxylic acid tert-butyl ester (60.3 mg, 0.136 mmol) and 4M HCl/dioxane (3 mL) in CH2Cl2 (3 mL) were stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude material was purified by reverse phase preparative HPLC-MS to obtain 5-ethynyl-3-(4-piperazin-1-ylmethylphenyl)-2H-isoquinolin-1-one as an off-white solid (16.0 mg, 34%).
Reaction SMILES: C(OCCOC[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:22])[C:12]=2[N:11]=[CH:10]1)(=O)C.N>CO>[N:9]1[CH:10]=[N:11][C:12]2[C:21]=1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:14][C:13]=2[NH2:22]
Reactant: CC(=O)OCCOCn1cnc2c(N)nc3ccccc3c21
Agent: N
Solvent: CO
Product: Nc1[nH]c2ccccc2c2ncnc1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 2.1 g portion of 1-[(2-acetoxyethoxy)-methyl]-1H-imidazo[4,5-c]quinolin-4-amine was combined with 25 mL of 15% ammonia in methanol and stirred at room temperature for about 16 hours. The resulting precipitate was collected, rinsed with ether and dried to provide 1.1 g of a solid. This solid was recrystallized from 50 mL of ethanol to provide 0.8 g of 1-[(2-hydroxyethoxy)]methyl-1H-imidazo[4,5-c]quinolin-4-amine as a yellow crystalline solid, m.p. 210°-212° C. Analysis: Calculated for C13H14N4O2 : %C, 60.4; %H, 5.5; %N, 21.7; Found: %C, 60.3; %H, 5.5; %N, 21.5.