Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:3][CH2:2]1.[CH3:11][C:12]1([CH3:21])[CH2:17][C:16](=O)[CH2:15][C:14]([CH3:20])([CH3:19])[NH:13]1>CO>[CH3:11][C:12]1([CH3:21])[CH2:17][CH:16]([NH:10][CH2:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:15][C:14]([CH3:20])([CH3:19])[NH:13]1
Reactant: NCCCN1CCOCC1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Solvent: CO
Product: CC1(C)CC(NCCCN2CCOCC2)CC(C)(C)N1

Procedure:
288.4 g (2 mol) of 3-morpholinopropylamine, 310.5 g (2 mol) of 2,2,6,6-tetramethyl-4-piperidone and 300 ml of methanol are introduced into a 2 litre autoclave; 15 g of 5% Pt-on-carbon are added, and hydrogenation is carried out at 60 bar and 60° C. until the absorption of hydrogen ceases (about 15 hours).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]([CH3:43])=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[CH:17]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH:26]=O)=[CH:24][CH:25]=2)[CH:19]=1)=[O:13].[NH:44]1[CH2:49]COC[CH2:45]1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:13])[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([CH2:26][N:44]([CH3:49])[CH3:45])=[CH:24][CH:25]=2)[CH:17]=[C:16]([N:28]([CH3:42])[CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)[C:15]=1[CH3:43]
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)nc3)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a stirred solution of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-formylpyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (1 equiv.) and morpholine (5 equiv.) in methanol (5 mL for 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 4 h. Then reducing agent NaBH3CN (1 equiv.) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and residue purified by column chromatography over silica gel affording desired tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-((dimethylamino)methyl)pyridin-3-yl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate. This compound was then dissolved in DCM (5 mL) and cooled to 0° C. TFA (2 mL) was added to it. The reaction mixture was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was purified by solvent washings to afford the title compound (0.06 g, 40%). LCMS: 517.25 (M+1)+; HPLC: 99.07% (@254 nm) (Rt; 3.913; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.48 (s, 1H), 10.08 (bs, 1H), 8.97 (s, 1H), 8.57 (bs, 1H), 8.23 (d, 2H, J=7.6 Hz), 8.18 (s, 1H), 7.60 (d, 1H, J=8 Hz), 7.50 (s, 1H), 7.34 (s, 1H), 5.87 (s, 1H), 4.49 (d, 2H), 4.30 (s, 2H), 3.25 (d, 2H), 3.16 (s, 1H), 2.89 (m, 2H), 2.83 (s, 6H), 2.64 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H), 2.10 (s, 3H), 1.81 (bs, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]([C:13]#[N:14])=[C:9](SC)[N:10]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1>C(#N)C>[OH:28][CH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:20]([C:9]2[N:10]=[C:5]([CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[CH3:1])[NH:6][C:7](=[O:15])[C:8]=2[C:13]#[N:14])[CH2:21][CH2:22]1
Reactant: OCCC1CCNCC1
Reactant: CSc1nc(Cc2ccccc2C)[nH]c(=O)c1C#N
Solvent: CC#N
Product: Cc1ccccc1Cc1nc(N2CCC(CCO)CC2)c(C#N)c(=O)[nH]1
Temperature: 25 °C

Procedure:
0.1 g (0.37 mmol) of 2-(2-methylbenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.14 g (1.1 mmol) of 2-(4-piperidinyl)ethan-1-ol in 3 ml of acetonitrile at 90° C. under argon for five days. After cooling to room temperature, the crude product is purified by preparative HPLC. 13 mg (10% of theory) of the title compound are obtained as a colourless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[NH:13][C:12]1=[O:19].C(O[Cl:25])(C)(C)C>CO>[Cl:25][N:13]1[C:14]([CH3:17])([CH3:18])[C:15](=[O:16])[N:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]1=[O:19]
Reactant: CC(C)(C)OCl
Reactant: COCCOCCOCCN1C(=O)NC(C)(C)C1=O
Solvent: CO
Product: COCCOCCOCCN1C(=O)N(Cl)C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.9 %

Procedure:
To a 0° C. solution of 3-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-5,5-dimethylimidazolidine-2,4-dione (900 mg, 3.3 mmol) in methanol (80 ml) was added tert-butylhypochlorite (220 mg, 2.0 mmol). The mixture was stirred for 1 hour at 0° C. The reaction mixture was checked for completion by high pressure liquid chromatography. The reaction mixture was concentrated in vacuo, and crude material was purified by preparative-high pressure liquid chromatography to give 30 mg (3%) of the title compound. 1H NMR (D2O, 400 MHz) δ 3.79 (t, J=4.8 Hz, 2H), 3.73 (t, J=4.8 Hz, 2H), 3.69-3.58 (m, 8H), 3.37 (s, 3H), 1.49 (s, 6H); LRMS (ESI/APCI) m/z 309 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:23][O:24][CH:25]([O:33][CH3:34])[CH2:26][NH:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([N:27]([CH2:26][CH:25]([O:33][CH3:34])[O:24][CH3:23])[C:17](=[O:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12][C:11]2[CH:20]=[CH:21][CH:22]=[C:9]([C:7]3[CH:6]=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)[CH:10]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(C)n1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Reactant: COC(CNC1CCCC1)OC
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C(C)C)c2)c1)C1CCCC1)OC

Procedure:
The subtitled compound (140 mg) was prepared from 3-(3-(1-isopropyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 20 Step iii)] and N-(2,2-dimethoxyethyl)cyclopentanamine [Preparation 9] using a similar method to that described in Example 18, Step iii). MS [M+H-MeOH]+=426 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.01 and 8.00 (2×s, 1H), 7.79 (s, 1H), 7.40 (s, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 4.56 and 4.37 (2×t, J=5.1 Hz, 1H), 4.53 (septet, J=6.8 Hz, 1H), 4.26-4.16 (m, 1H), 3.76-3.64 (m, 4H), 3.35 and 3.22 (2×d, J=5.1 Hz, 2H), 3.34 (s, 3H), 3.32 (s, 3H), 2.84 (t, J=6.7 Hz, 2H), 2.65 (t, J=6.2 Hz, 2H), 1.82-1.45 (m, 8H), 1.51 (d, J=6.8 Hz, 6H); a ˜2:1 mixture of rotamers is observed.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:18][NH:19][CH:10]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(C=Cc1cccs1)c1ccc(Br)cc1
Solvent: O
Solvent: CCO
Product: Brc1ccc(C2=CC(c3cccs3)NN2)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
1-(4-Bromophenyl)-3-(2-thienyl)-2-propen-1-one (3.0 g, 10.2 mmol) and hydrazine hydrate (1.0 g, 20 mmol) were added to ethanol (30 ml) and heated under reflux for 3 hours. After the mixture was allowed to cool to room temperature, the solvent was distilled off to obtain 3.0 g (98%) of the desired 3-(4-bromophenyl)-5-(2-thienyl)-pyrazoline in the form of a resinous material.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:29][CH2:30][CH3:31])=[O:22])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: O=C(O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
A mixture of 2-benzyl-4-(3-carboxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (50 mg), 1-iodopropane (48 mg) and potassium carbonate (58 mg) in N,N-dimethylformamide (1 ml) was stirred at room temperature for 2 hours. The mixture was poured into ethyl acetate and washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to preparative thin layer chromatography (hexane-ethyl acetate, 1:1) to afford 2-benzyl-3-oxo-4-(3-propyloxycarbonylphenyl)-3,4-dihydropyrido[2,3-b]pyrazine (18 mg) as powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:10]=[C:9]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:8]=[C:7]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[C:4]=1[C:5]#[N:6].C=O.[C:31]([BH3-])#N.[Na+]>CO>[NH2:2][C:3]1[N:10]=[C:9]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][CH:20]2[CH2:21][CH2:22]2)[CH:8]=[C:7]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([CH3:31])[CH2:24]2)[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(C2CCCNC2)cc(-c2c(O)cccc2OCC2CC2)nc1N
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
To a stirred solution of 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]4-(3-piperidinyl)nicotinonitrile hydrochloride (200.0 mg, 0.50 mmol) in MeOH were added formaldehyde (0.5 mL) and sodium cyanoborohydride (40.8 mg, 0.65 mmol) and stirred for 2 hrs at room temperature. The reaction was quenched by an addition of water, extracted with ethyl acetate, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane and dried. The crude product was purified by preparative silica gel TLC (5% MeOH in dichloromethane) to give 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methyl-3-piperidinyl)nicotinonitrile as a yellow solid. (28.5 mg, yield 15%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C@H:22]([CH2:37][C:38]3[CH:46]=[C:45]([CH3:47])[C:44]4[C:40](=[CH:41][N:42](COCC[Si](C)(C)C)[N:43]=4)[CH:39]=3)[C:23](=[O:36])[N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:26][CH2:25]3)=[O:20])[CH2:15][CH2:14]1)=[CH:7]2.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C@H:22]([CH2:37][C:38]3[CH:39]=[C:40]4[C:44](=[C:45]([CH3:47])[CH:46]=3)[NH:43][N:42]=[CH:41]4)[C:23](=[O:36])[N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:28][CH2:29]3)=[O:20])[CH2:17][CH2:18]1)=[CH:7]2
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
(R)-3-(7-Methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (122 mg, 0.16 mmol) was dissolved in ethyl acetate (2 mL). Hydrochloric acid (4 N in dioxane, 3.0 mL) was added to the mixture. The reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated en vacuo and purified by preparatory HPLC. Organic solvents were removed from the product fractions. The remaining aqueous solution was made basic with aqueous sodium bicarbonate and was extracted with ethyl acetate (2×). The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated in vacuo. The title compound was obtained as an off-white solid in 59% yield. 1H NMR (500 MHz, DMSO-d6): δ 13.03 (s, 1H), 11.78 (s, 1H), 7.99 (s, 1H), 7.70 (m, 1H), 7.46 (m, 3H), 7.34 (dd, J=10.81, 8.09, 1H), 7.15 (m, 1H), 7.06 (s, 1H), 5.43 (m, 1H), 4.34 (m, 1H), 4.17 (m, 1H), 3.88 (m, 1H), 3.06 (m, 2H), 2.97 (m, 2H), 2.83 (m, 3H), 2.50 (m, 3H), 2.36 (m, 2H), 2.27 (m, 1H), 2.05 (m, 2H), 1.82 (d, J=12.51, 2H), 1.68 (m, 1H), 1.39 (m, 10H), 0.78-0.26 (m, 1H). Mass spec.: 643.3425 (MH)+.
Reaction SMILES: CC(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([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])[CH2:12][CH:13]([CH3:15])[CH3:14])(C)C.Cl.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].C(O)C>O1CCOCC1>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[NH2:7][CH2:8][CH2:9][CH2:10][CH:11]([NH: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])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC(CCCNC(=O)OC(C)(C)C)Nc1cc(C(F)(F)F)ccc1C#N
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)CC(CCCN)Nc1cc(C(F)(F)F)ccc1C#N

Procedure:
4-[[2-Cyano-5-(trifluoromethyl)phenyl]amino]-6-methylheptylcarbamic acid 1,1-dimethylethyl ester (250 mg, 0.6 mmol) was stirred in a 4M solution of hydrogen chloride in dioxan (15 ml) for 3 h. The mixture was then concentrated to dryness and the residue treated with saturated aqueous sodium carbonate (50 ml). The products were extracted into diethyl ether (100 ml), and the extract dried over magnesium sulphate. Concentration of the extract gave a gum that was purified on silica gel eluting with 10% methanolic ammonia (7N) in dichloromethane. The product from the column was converted into a fumarate salt by addition of one equivalent of fumaric acid in the minimum amount of ethanol. The title compound was isolated as a colourless solid (80 mg, 31%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])[C:15]([OH:17])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:39][CH3:40]>>[CH2:39]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH2:33][NH:32][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:20]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH:13]=1)[CH3:40]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1OC/C=C(\C)CCC=C(C)C
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)c(OC/C=C(\C)CCC=C(C)C)c1
Yield: 72 %

Procedure:
In a manner identical to Example 15, 3,4-digeranyloxybenzoic acid (2.13 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7mn), thereby yielding 1.93 g (72%) of the aimed compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:21][C:22]([C:25]1[CH:26]=[CH:27][C:28]([O:33][C:34]([F:37])([F:36])[F:35])=[C:29]([CH:32]=1)[CH:30]=O)([F:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:30][C:29]2[CH:32]=[C:25]([C:22]([F:24])([F:21])[CH3:23])[CH:26]=[CH:27][C:28]=2[O:33][C:34]([F:35])([F:37])[F:36])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(F)(F)c1ccc(OC(F)(F)F)c(C=O)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 156.8 %

Procedure:
To a stirred solution of Compound 12 (500 mg, 1.81 mmol) and Compound 25 (552 mg, 2.17 mmol) in dry CH2Cl2 (10 ml) was added sodium triacetoxyborohydride (1.15 g, 5.43 mmol) portionwise at room temperature. Then to this was added acetic acid (109 mg, 1.81 mmol) at same temperature. The reaction mixture was stirred at room temperature for 66 h. The reaction mixture was basified to pH10-11 with 10% NaOH aq. with ice-cooling. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with brine, dried (MgSO4), and concentrated in vacuo to give crude product (1.46g) as a pale yellow oil. This was employed for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1ccc(Br)cc1
Product: CCOC(=O)c1ccc(-c2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (2.01 g) and ethyl 4-bromobenzoate (2.29 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)[CH:9]=[CH:10][CH:11]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]2[CH:21]=[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:7]=3)[N:13]=[C:14]2[CH:19]=1
Reactant: Cc1ccn2cc(-c3cccc(OCCCCl)c3)nc2c1
Reactant: C1CCNCC1
Product: Cc1ccn2cc(-c3cccc(OCCCN4CCCCC4)c3)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (271 mg) and piperidine (2.0 mL) were heated at 100° C. for 2 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (10 mL) and the organic portions combined and washed with brine (10 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (193 mg). 1H-NMR (CD3OD) 8.27 (d, J=7.0 Hz, 1H), 8.08 (s, 1H), 7.46 (m, 2H), 7.31 (m, 2H), 6.88 (m, 1H), 6.76 (m, 1H), 4.09 (t, J=6.0 Hz, 2H), 2.58 (m, 6H), 2.42 (s, 3H), 2.04 (m, 2H), 1.65 (m, 4H), 1.51 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: C1COCCN1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2occc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
2,4-Dichlorofuro[3,2-d]pyrimidine 37 (23 mg, 1.0 eq) was suspended in methanol (1.7 ml) and treated with morpholine (0.09 ml, 4.0 eq). Reaction mixture was stirred at room temperature for 2 h, before being quenched with saturated aq. NaHCO3. Mixture was extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated to yield 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 (14 mg, 48%) which was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]3[CH2:14][CH2:13]3)[CH:11]=1)[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]2([CH3:18])[CH3:17].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:12]1([C:10]2[CH:11]=[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:3]=[C:4]3[C:9]=2[O:8][C:7]([CH3:16])([CH3:15])[CH2:6][C:5]3([CH3:18])[CH3:17])[CH2:14][CH2:13]1
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C3CC3)c2O1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C3CC3)c2O1

Procedure:
Following general procedure D and using 6-bromo-8-cyclopropyl-2,2,4,4-tetramethyl chroman (Intermediate 32, 0.376 g, 1.22 mmol), (trimethylsilyl)acetylene (4 mL, 28 mmol), triethyl amine (3 mL), anhydrous tetrahydrofuran (5 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol), the title compound was obtained as an oil (0.173 g, 43%).
Reaction SMILES: Br[C:2]1[C:3]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:11]=[C:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[C:27]([N:29](C)C)=O>[C-]#N.[Zn+2].[C-]#N.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>[C:27]([C:2]1[C:3]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:11]=[C:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1)#[N:29]
Reactant: CC(=O)N(C)C
Reactant: COc1ncc(Br)c2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ncc(C#N)c2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-(7-bromo-1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (100 mg), zinc cyanide (41.8 mg) and tetrakis(triphenylphosphine)palladium(0) (54.9 mg) in DMA was stirred under microwave irradiation at 120° C. for 30 min. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (61.7 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:30](=[O:31])[CH2:29][CH2:28][C:27]4=[O:32])[CH2:20][CH2:19]3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].I[CH2:35][CH3:36]>>[CH2:35]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:15])([CH3:16])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:27](=[O:32])[CH2:28][CH2:29][C:30]4=[O:31])[CH2:20][CH2:19]3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH3:36]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1O
Reactant: CCI
Product: CCOc1cc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)ccc1OC

Procedure:
Prepared analogously as described for example 5 using 1-(2-{4-[3-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl)}-2-oxoethyl)pyrrolidine-2,5-dione (compound A4) and iodoethane as starting compounds.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
10.6 g (57 mmol) of N-tert.butoxycarbonyl-piperazine are dissolved in 100 ml of dichloromethane and combined with 10.7 g (63 mmol) of 4-nitrobenzylchloride and 24 ml (171 mmol) of triethylamine. The mixture is refluxed for 12 hours. After cooling to ambient temperature the reaction solution is washed several times with water. The organic phase is dried over magnesium sulphate and then evaporated to dryness.