Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:9][N:8]2[C:10]3[CH:11]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]=[CH:14][C:15]=3[C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:7]2[C:6]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:30][C:5]=2[O:4][CH2:3]1.C(OC)(OC)OC.[CH3:46][N:47]([CH2:55][CH:56]=O)[C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51].[BH3-]C#N.[Na+]>>[C:50]([O:49][C:48]([N:47]([CH3:46])[CH2:55][CH2:56][NH:1][C@@H:2]1[CH2:9][N:8]2[C:10]3[CH:11]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]=[CH:14][C:15]=3[C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:7]2[C:6]2[CH:27]=[CH:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:30][C:5]=2[O:4][CH2:3]1)=[O:54])([CH3:53])([CH3:52])[CH3:51]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N)COc1cc(OCc2ccccn2)ccc1-3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NCCN(C)C(=O)OC(C)(C)C)COc1cc(OCc2ccccn2)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (7R)-7-amino-14-cyclohexyl-3-(pyridin-2-ylmethoxy)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate was dissolved in HC(OMe)3 (50 eq) and a solution of tert-butyl methyl(2-oxoethyl)carbamate (1.6 eq, prepared according to Tetrahedron 2002, 58, 1719-1737) in HC(OMe)3 (50 eq) was added. The mixture was stirred overnight at RT to allow formation of the imine. All volatiles were evaporated and the residual material was dissolved in MeOH/HOAc (0.05 M). NaCNBH3 (1 eq) was added and the mixture was stirred at RT for 1 h. Some formation of the N-formyl product was observed alongside formation of the desired product. The solution was used directly in the next step. (ES+) m/z 669 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]([O:23]C(C)(C)C)=O)=[CH:14][CH:13]=1.ClC(OCC)=O.Cl[CH:35](F)[F:36]>C(O)(=O)C.O1CCCC1>[F:36]/[CH:35]=[C:20](\[CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)/[CH2:21][OH:23]
Reactant: FC(F)Cl
Reactant: CC(C)(C)OC(=O)CCCc1ccc(F)cc1
Agent: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC/C(=C/F)CCc1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
Cool a tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (545 kg, 2M, 877 mol) to -10° C. Slowly add, t-butyl 4-(p-fluorophenyl)butyrate (84.1 kg, 80% by weight in toluene, 353 mol). After 15 minutes, slowly add ethyl chloroformate (38.6 kg, 356 mol) at such a rate that the reaction temperature is maintained at or below -5° C. After 20 minutes, warm the reaction mixture to 40° C.-45° C. Seal the reaction vessel and add chlorodifluoromethane (38.15 kg, 445 mol) to the head space. After 1 hour, cool to 15° C.-20° C. and vent the reaction vessel. Add a solution of acetic acid (421 kg, 20% in water) and stir. After 30 minutes, separate the aqueous layer and evaporate the organic layer in vacuo to obtain a residue. Add toluene (45 kg) and evaporate in vacuo until the internal temperature of the reaction vessel is 55° C. to obtain the title compound as a toluene solution.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19])[CH2:6]2)=[O:4].C(N(CC)CC)C.[CH2:38]([N:42]([CH2:45][CH2:46][CH2:47][CH3:48])[S:43]Cl)[CH2:39][CH2:40][CH3:41]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([N:20]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[S:43][N:42]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:19])[CH2:6]2)=[O:4]
Reactant: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Reactant: CCCCN(CCCC)SCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(CCCC)SN(C(=O)N1CC2(C(=O)OC)CCc3ccccc3C2=N1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Step B (Example 1) (0.4 g, 0.96 mmol) in 8 ml methylene chloride cooled to 0° C. was added triethylamine (0.15 g) and dibutylaminosulfenylchloride (0.2 g). The reaction mixture was warmed to room temperature and stirred for one hour. The mixture was subjected to silica gel column chromatography using hexane-ether (6:1) as the eluent. The title compound was obtained (0.24 g)in high purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[O:14])[N:12]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1.[NH4+].[Cl-].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:16][CH2:17][C:18]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)([OH:21])[CH2:19][CH2:20]2)=[O:14])[N:12]=1
Reactant: O=C1CCN(C(=O)c2cn(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)n2)CC1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1)N1CCC(O)(c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of 1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}-4-piperidinone (0.1 g, 0.24 mmol, prepared as described in Example 13) in THF (4 mL) was added dropwise to a solution of 4-fluorophenylmagnesium bromide (0.6 mL, 0.60 mL) at −78° C. The mixture was stirred at −78° C. for 2 h then allowed to warm up to 30° C. Saturated NH4Cl (3 mL) was added slowly followed by water (3 mL). The mixture was extracted with ethyl acetate (3×20 mL) and dried over MgSO4. The product (0.056 g, 46%) was isolated by column (50% ethyl acetate in hexane). MS (Electrospray) 510.1 (M)+; 1H NMR (300 MHz, CD2Cl2) δ 7.81 (s, 1H), 7.50-7.24 (m, 8H), 7.10-6.98 (m, 4H), 5.33-5.17 (m, 1H), 4.74-4.57 (m, 1H), 3.68 (t, 1H), 3.31 (t, 1H), 2.15 (br, 2H), 1.83 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH:19]([OH:22])([CH3:21])[CH3:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:22][CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CC(C)O
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Oc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, isopropyl alcohol and DBU in DME. EI-MS m/e (%): 244 (M+, 40), 202 ([M—C3H6]+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14]([CH2:19]Br)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([C:28]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:21]([C:28]1([OH:34])[CH2:33][CH2:32][N:31]([CH2:19][CH:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[O:15]2)[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: BrCC1CCc2cc(OCc3ccccc3)ccc2O1
Reactant: OC1(Cc2ccccc2)CCNCC1
Solvent: Cc1ccccc1
Product: OC1(Cc2ccccc2)CCN(CC2CCc3cc(OCc4ccccc4)ccc3O2)CC1
Yield: 86.5 %

Procedure:
(RS)-6-Benzyloxy-2-bromomethyl-chroman (0.52 g, 1.56 mmol) and 4-(benzyl)-piperidin-4-ol (0.66 g, 3.43 mmol) in toluene (20 ml) was refluxed for 18 hr under argon. After removal of the solvent the crude mixture was chromatographed over SiO2 (Merck 230-400 mesh) CH2Cl2—MeOH—NH4OH (100:5:0.25) to afford the title compound (RS)-4-benzyl-1-(6-benzyloxy-chroman-2-ylmethyl)-piperidin-4-ol as a yellow oil (0.6 g, 1.35 mmol, 86%), MS: m/e=444.5 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cccc(C)c1
Agent: N
Product: Cc1cccc(-c2cc(-c3cncc(F)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-3-methylbenzene (Aldrich, 58 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 2.44 (s, 3H), 7.29-7.38 (m, 2 H), 7.42 (t, J=7.6 Hz, 1H), 7.64-7.81 (m, 2H), 8.17 (ddd, J=9.4, 2.8, 1.7 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.97 (t, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 255 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>>[OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: O=[N+]([O-])O
Product: O=C(O)c1cnc(O)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a 250 mL flask were added 6-hydroxynicotinic acid (20 g, Aldrich) and 100 mL of red fuming nitric acid. The mixture was slowly heated to 50° C. (bath temperature) and stirred at this temperature for 8 h. Then the temperature was slowly raised to 80° C. and the mixture was stirred for another 7 h. The mixture was cooled to rt overnight and the yellow precipitate was collected by filtration, washed with water (10 mL) and dried. LC-MS: >95% pure. 1H NMR (CD3OD, 400 MHz): δ=8.45 (d, J=2.5 Hz, 1H), 8.85 (d, J=2.5 Hz, 1H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])([C:19]#[N:20])[C:17]#[N:18].O>C(Cl)(Cl)Cl>[F:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])([C:19]#[N:20])[C:17]#[N:18]
Reactant: CCN(CC)S(F)(F)F
Reactant: N#CC(C#N)(CCCCCO)CCC(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#CC(C#N)(CCCCCF)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 9 h
Yield: 29.8 %

Procedure:
0.29 g of diethylaminosulfur trifluoride was dissolved in 5 ml of chloroform and thereto was added dropwise at 0° C. 0.40 g of 2-(5-hydroxypentyl)-2-(3,3,3-trifluoropropyl)malononitrile dissolved in 3 ml of chloroform. The mixture was stirred at room temperature for 9 hours. Thereafter, water was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.12 g of 2-(5-fluoropentyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (55)).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([C:13]3[N:17]4[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[NH:25]([C:27]([NH2:29])=[O:28])[NH2:26]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([C:13]3[N:17]4[N:18]=[C:19](/[C:22](=[N:26]/[NH:25][C:27]([NH2:29])=[O:28])/[CH3:23])[CH:20]=[CH:21][C:16]4=[N:15][CH:14]=3)[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: CC(=O)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Reactant: NNC(N)=O
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Yield: 62 %

Procedure:
The title compound (14.0 mg, 59%) was synthesized from 1-(3-(1-(1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (20.0 mg, 0.06 mmol) and hydrazinecarboxamide (13.97 mg, 0.13 mmol) using the same procedure as described in the synthesis of example 69. 1H-NMR (400 MHz, CDCl3) δ ppm 8.33 (s, 1H), 7.87 (m, 2H), 7.66 (m, 3H), 7.32 (m, 2H), 4.74 (q, 1H), 4.03 (s, 3H), 2.24 (s, 3H), 1.84 (d, 3H). LCMS (method A): [MH]+=377, tR=4.70 min.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][C:22]2=[CH:23][N:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([C:28]([NH:10][NH:9][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:8])=[O:29])[NH:25][C:22]2=[CH:23][N:24]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NNC(=O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NNC(=O)c1cc2cc(Cl)ncc2[nH]1)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of nicotinic acid hydrazide (35 mg, 0.25 mmol) in DMF (5 mL) was added triethylamine (88 μL, 0.64 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 8, 50 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol) and EDCI (50 mg, 0.28 mmol). The mixture was allowed to stir at rt for 16 h. The solvent was removed in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give an oil, which was purified by flash chromatography on silica gel (dichloromethane/methanol, 9/1) to give the title compound. m/z (ES+)=316 [M+H]+; RT=2.62 min.
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3].S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH:2]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cccc(NS(C)(=O)=O)c1
Solvent: ClCCl
Product: CC(Cl)c1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
650 mg (3.02 mmol) of rac-N-[3-(1-hydroxyethyl)phenyl]methanesulfonamide (Example 87A) were initially charged in 9 ml of dichloromethane. At 0° C., 1.08 g (9.07 mmol) of thionyl chloride were added dropwise, and the reaction solution was stirred at RT for 3 h. The reaction solution was evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([N:14]=[C:15]=[S:16])[N:8]=[C:7]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C:6]=2[CH:22]=1.[N:23]1([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([NH2:39])=[CH:31][CH:30]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([NH:14][C:15]([NH:39][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:30][CH:31]=3)=[S:16])[N:8]=[C:7]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C:6]=2[CH:22]=1
Reactant: Nc1ccc(N2CCOCC2)c2ccccc12
Reactant: CN1C(=O)C(N=C=S)N=C(c2ccsc2)c2cc(Cl)ccc21
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(NC(=S)Nc2ccc(N3CCOCC3)c3ccccc23)N=C(c2ccsc2)c2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
This reaction was carried out in a multiwell plate. As illustrated in the scheme above, aA mixture of 7-chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-(3-thienyl)-2H-1,4-benzodiazepin-2-one (156 μL of a 0.128 M solution in (CH2Cl)2, 0.020 mmol), 4-(4-morpholinyl)-1-naphthalenamine (44 μL of a 0.5 M solution in DMA, 0.022 mmol), and (CH2Cl)2 (300 μL) was agitated and heated at 70° C. for 22 h. The reaction was cooled and concentrated in vacuo, and the residue was redissolved in DMA (25 μL) and (CH2Cl)2 (275 μL). Polyamine resin HL (NovaBiochem) was added (20 mg of 4.53 mmol/g, 0.091 mmol), and the mixture was agitated at room temperature overnight. The resin was removed by filtration and washed with additional (CH2Cl)2 and MeOH. The filtrate was concentrated in vacuo to provide the title compound. MS (ESI) (M+H)+=576.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.S(Cl)([Cl:15])=O>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([Cl:15])=[O:12])=[CH:3]1
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Reactant: O=S(Cl)Cl
Product: Cc1cc(C(=O)Cl)cn(C)c1=O
Temperature: 60 °C
Yield: 100 %

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (500.000 mg; 2.991 mmol) is suspended in thionyl chloride (2.000 ml; 27.536 mmol) and heated for 2 h at 60° C. The reaction mixture is concentrated under reduced pressure. And used in the next reaction without further purification (Yield: 100%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: c1cc(CN2CCCCC2)cc(OCCCNc2ccc3ccccc3n2)c1
Yield: 25.6 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.0 g) and 2-chloroquinoline (1.31 g) were fused at 140° C. for two hours. The oily residue was taken up in methanol/water (5:50), neutralised with solid potassium carbonate and extracted into chloroform. The chloroform extract was dried, evaporated under reduced pressure and subjected to medium pressure liquid chromatography (chloroform) to afford the title product as an oil (0.77 g). This was treated with maleic acid to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]quinoline dimaleate (0.4 g), m.p. 148°-150° C. (recrystallised from ethanol).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[NH:8][N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6])[CH3:3].[CH2:17](I)[CH3:18]>C(O)C.C([O-])C.[Na+]>[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:17][CH3:18])[N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cn[nH]c1C(=O)OCC
Reactant: CCI
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnn(CC)c1C(=O)OCC
Yield: 30.9 %

Procedure:
Sodium ethanolate solution was freshly prepared by dissolving sodium (240 mg) in ethanol (30 ml). 2H-Pyrazole-3,4-dicarboxylic acid diethyl ester (800 mg, 3.77 mmol) was dissolved in this sodium ethanolate solution (11 ml) and stirred for 10 min at RT, before ethyl iodide (1.4 g, 9 mmol) was added dropwise. After the completion of the addition, the mixture was heated to reflux until all starting material was consumed (1 h). The solvent was then evaporated, the residue was taken up in ethyl acetate and washed (water). The organic layer was dried (Na2SO4), evaporated, and the title compound (280 mg, 31%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). (The regioisomeric 1-ethyl-1H-pyrazole-3,4-dicarboxylic acid diethyl ester can also be isolated, and can be distinguished from the desired product by NOE-'H-NMR.)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.OC[C@H]1CCCN1C(OC(C)(C)C)=O.[F:39][C:40]1[CH:41]=[C:42]([CH:59]=[CH:60][CH:61]=1)[O:43][C:44]1[CH:49]=[CH:48][C:47](B2OC(C)(C)C(C)(C)O2)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:47]3[CH:46]=[CH:45][C:44]([O:43][C:42]4[CH:59]=[CH:60][CH:61]=[C:40]([F:39])[CH:41]=4)=[CH:49][CH:48]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3)cc2)OC1(C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), prepared as described in Example 1 except in the Mitsunobu reaction using (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate instead of (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (254 mg, 0.81 mmol, 1.20 equiv), tetrakis(triphenylphosphane)palladium (47 mg, 0.04 mmol, 0.06 equiv), ethylene glycol dimethyl ether (50 mL), sodium carbonate (180 mg, 1.70 mmol, 2.50 equiv), and water (10 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum and extracted with dichloromethane. The organic layers were combined, dried and concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane/methanol (50/1) to give 0.27 g (79%) of tert-butyl (2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][N:37]([CH3:42])[CH:38]1[CH2:41][NH:40][CH2:39]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:40]3[CH2:41][CH:38]([N:37]([CH3:42])[CH3:36])[CH2:39]3)=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CN(C)C1CNC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)C1
Temperature: 80 °C
Yield: 87 %

Procedure:
A solution of ethyl 5{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (360 mg, 0.91 mmol) and triethylamine (370 mg, 3.65 mmol) in ethanol (5 ml) was treated with N,N-dimethyl-3-azetidinamine (J.Med.Chem.;36; 801; 1993) (300 mg, 0.91 mmol) and the resulting mixture was heated at 80° C. under a nitrogen atmosphere for 16 hours. The mixture was partitioned between ethyl acetate (150 ml) and saturated aqueous ammonium chloride solution (150 ml). The organic layer was washed with saturated ammonium chloride solution (150 ml), water (150 ml) and brine (150 ml), dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate:diethylamine (87.5:12.5:0.25) gradually changing to pentane:ethyl acetate: diethylamine (50:50:1) to afford the title compound as a colourless oil (355 mg).