Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C@H:27]1[N:35]2[C@@H:30]([CH2:31][CH2:32][CH:33](P(=O)(OCC)OCC)[C:34]2=[O:36])[CH2:29][CH2:28]1.C(O)C>O1CCCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C@H:27]1[N:35]2[C@@H:30]([CH2:31][CH2:32]/[C:33](=[CH:8]\[C:7]3[CH:10]=[CH:11][C:12]([N:13]4[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]4)=[C:5]([O:4][CH3:3])[CH:6]=3)/[C:34]2=[O:36])[CH2:29][CH2:28]1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cc(F)ccc3F)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cc(F)ccc4F)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
Lithium hydroxide (0.443 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (1.0 g) and diethyl [(3S,8aR)-3-(2,5-difluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (4.1 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 1.85 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: ON=[C:3]([C:8]1[CH:9]=[N:10][S:11][CH:12]=1)[C:4]([O:6]C)=[O:5].C=[O:14].Cl>O>[S:11]1[CH:12]=[C:8]([C:3](=[O:14])[C:4]([OH:6])=[O:5])[CH:9]=[N:10]1
Reactant: COC(=O)C(=NO)c1cnsc1
Reactant: C=O
Agent: Cl
Solvent: O
Product: O=C(O)C(=O)c1cnsc1
Reaction time: 7 h

Procedure:
A mixture of methyl 2-hydroxyimino-2-(isothiazol-4-yl)-acetate (anti isomer) (3.41 g.), 36% aqueous solution of formaldehyde (24 ml.), conc. hydrochloric acid (12 ml.) and water (24 ml.) was stirred for 7 hours at 90° to 100° C. The reaction mixture was allowed to stand overnight in a refrigerator to precipitate crystals. The crystals were collected by filtration, washed with a small amount of ice-water and then dried to give 2-(isothiazol-4-yl)glyoxylic acid (2.09 g.). The mother liquor was extracted with ethyl acetate to give the same compound (0.34 g.), mp 145° to 148° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]2O.O=P(Cl)(Cl)[Cl:24]>>[F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]2[Cl:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(OC(F)(F)F)cc2c1O
Product: CCOC(=O)c1cnc2ccc(OC(F)(F)F)cc2c1Cl
Reaction time: 0.25 h

Procedure:
6-Trifluoromethoxy-4-hydroxy-3-ethoxycarbonylquinoline (3 g, 10 mmol) and POCl3 (8 mL) were mixed together and the mixture was heated at reflux for 6 h. The excess POCl3 was removed under vacuum. The solid residue was suspended in ice-cold 1N NaOH and the mixture was stirred for 15 min. The solid was filtered off, washed several times with water and dried over P2O5 to give 6-trifluoromethoxy-4-chloro-3-ethoxycarbonylquinoline as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O>[CH:1]1([CH2:7][C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](CC2CCCCC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CC1CCCCC1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A solution of cis-methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate, from a preparation of Example 20, Step 1 (1.28 g, 3.62 mmol) in MeOH (3 mL) was added dropwise to a solution of NaOH (0.159 g) in MeOH/H2O (3 mL/0.2 mL) at −30° C. After stirring for 10 minutes a solution of hydroxylamine hydrochloride (0.50 g, 7.24 mmol) and NaOH (0.29 g, 7.24 mmol) in methanol/water (5 mL/5 mL) was added at −30° C. Stirring was continued for 30 minutes at −30° C. The solution was added dropwise to HCl (6M) at 80° C. Stirred 30 minutes at 80° C. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through Celite® and the solvent was evaporated. Acidic reversed phase chromatography, gradient 35% to 75% acetonitrile gave cis-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.62 g, 53.1%). Chiral separation using Chiralpac IC, mobile phase heptane/isopropyl alcohol 80/20 at the temperature 40° C. gave (2R,4R)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.28 g), e.e. 98.5% and (2S,4S)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.27 g), e.e 98.5%. 1H NMR (600 MHz, cdcl3, RR) δ 0.67-0.88 (m, 2H), 0.98-1.20 (m, 5H), 1.28 (dd, 1H), 1.56 (dd, 5H), 1.75-1.86 (m, 2H), 1.92-2.06 (m, 2H), 2.87-2.99 (m, 1H), 3.02-3.15 (m, 1H), 3.65 (s, 3H), 3.88 (dd, 1H), 4.15 (p, 1H), 5.65 (d, 1H). [α]20D −30.7 (MeCN, c=1); 1H NMR (600 MHz, cdcl3, SS) δ 0.70-0.87 (m, 2H), 0.97-1.20 (m, 5H), 1.28 (dd, 1H), 1.51-1.65 (m, 5H), 1.77-1.85 (m, 2H), 1.96-2.05 (m, 2H), 2.87-2.96 (m, 1H), 3.03-3.14 (m, 1H), 3.65 (s, 3H), 3.88 (dd, 1H), 4.15 (p, 1H), 5.65 (d, 1H) [α]20D +29.9 (MeCN, c=1).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:10]([CH2:19]Br)=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=O.Cl.[C:22]([O:26][C:27](=[O:35])[C@H:28]([CH2:30][CH2:31][C:32](=[O:34])[NH2:33])[NH2:29])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:11]2[C:10]=1[CH2:19][N:29]([CH:28]([CH2:30][CH2:31][C:32](=[O:34])[NH2:33])[C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:35])[C:12]2=[O:14]
Reactant: COC(=O)c1cccc(Br)c1CBr
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCC(N)=O)N1Cc2c(Br)cccc2C1=O
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Triethylamine (4.66 g, 46.09 mmol) was added to a stirred suspension of methyl 3-bromo-2-bromomethylbenzoate (6.45 g, 20.95 mmol) and L-glutamine t-butyl ester hydrochloride (5.0 g, 20.95 mmol) in THF (100 mL). The mixture was heated to reflux for 18 hours. The mixture was cooled to room temperature and solvent was removed. The residue was dissolved in methylene chloride (100 mL) and washed with water (2×80 mL), brine (80 mL) and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (CH2Cl2:CH3OH 97.5:2.5) to afford tert-butyl 2-(4-bromo-1-oxoisoindolin-2-yl)-4-carbamoylbutanoate (3.97 g, 48%): 1H NMR (CDCl3) δ 7.74 (d, J=7.1 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 6.15 (s, 1H), 5.77 (s, 1H), 5.02-4.96 (m, 1H), 4.58 (d, J=17.4 Hz, 1H), 4.34 (d, J=17.4 Hz, 1H), 2.45-2.10 (m, 4H), 1.46 (s, 9H); 13C NMR (CDCl3) δ 173.83, 169.42, 168.74, 142.28, 134.70, 133.65, 129.80, 122.70, 117.75, 82.66, 54.29, 47.80, 32.27, 27.95, 25.54.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]Br.[OH-].[Na+]>C(O)(=O)C.CCOCC>[NH2:1][C:2]1[C:7]([Br:9])=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: Cc1ccc(N)nc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cnc(N)c(Br)c1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-picoline (5 g) in acetic acid (40 mL) at r.t. was added bromine (2.6 mL) slowly. After 1 h, the acid was neutralized by the careful addition of sodium hydroxide (10N) at 0°0 C. The resulting orange precipitate was dissolved in ether and washed successively with saturated potassium carbonate, saturated Na2S2O3 and brine, dried and concentrated. Flash chromatography (eluting with hexane/ethyl acetate, 3:2 v/v) of the residual solid provided the title compound as a pale yellow solid (7.1 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.Cl[C:32]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[O:33]>>[CH3:38][O:37][CH2:36][CH2:35][O:34][C:32](=[O:33])[NH:1][CH2:2][C@H:3]1[CH2:4][C@@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:6]1
Reactant: COCCOC(=O)Cl
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Product: COCCOC(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamic acid 2-methoxy-ethyl ester is prepared as described in Example 22 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and 2-methoxyethyl chloroformate (TCI America, Portland, Oreg., U.S.A.). Analytical HPLC: tR=7.02 min (Grad 2); ES-MS: m/eo=502.0.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[N:32]2[N:36]=[C:37]([CH:39]=O)[N:38]=[C:31]2[N:30]=1>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:39][C:37]3[N:38]=[C:31]4[N:30]=[C:29]([CH3:28])[CH:34]=[C:33]([CH3:35])[N:32]4[N:36]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Solvent: CO
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C(C)(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile (0.40 g, 1.1 mmol) in MeOH (7 mL) was added 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.19 g, 1.08 mmol) and borane-dimethylamine complex (76 mg, 1.3 mmol) and stirred at room temperature for 3 hours. The reaction was quenched with 10 mL saturated NH4Cl and 5 mL water. To this was added 20 mL CH2Cl2 and the pH of the aqueous phase was adjusted to 3. The layers were separated, and the aqueous layer was extracted with 3×30 mL 10% MeOH in CH2Cl2. The organic layers were combined, and dried over Na2SO4. After filtering off the solids, the liquid was concentrated by rotary evaporation to an oil. The oil was flash chromatographed, and the resulting product was further purified by preparatory HPLC. Yield: 28 mg, 5%. MS (ESI): 530 (M−H).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH:2]=1.O.NN>C(O)C>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCC#Cc1cccc(-c2ccccc2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCC#Cc1cccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
2-(5-(Biphenyl-3-yl)pent-4-ynyl)isoindoline-1,3-dione (0.11 g, 0.30 mmol) and hydrazine monohydrate (0.030 mL, 0.60 mmol) were taken up into ethanol (3 mL) and stirred at 80° C. for 2.5 hours. The resulting mixture was filtered and the solvent removed in vacuo to yield 5-(biphenyl-3-yl)pent-4-yn-1-amine, which was used in the next step without further purification. MH+ 236.2
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([OH:16])=[O:15])=[C:6]2[C:10]=1[O:9][CH:8]([CH2:11][O:12][CH3:13])[CH2:7]2.Cl[C:18]1[N:27]=[CH:26][C:25]2[N:24]([CH3:28])[C:23](=[O:29])[C@@H:22]([CH2:30][CH3:31])[N:21]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:20]=2[N:19]=1.Cl>C(O)C.O>[CH:32]1([N:21]2[C:20]3[N:19]=[C:18]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([C:14]([OH:16])=[O:15])=[C:6]5[C:10]=4[O:9][CH:8]([CH2:11][O:12][CH3:13])[CH2:7]5)[N:27]=[CH:26][C:25]=3[N:24]([CH3:28])[C:23](=[O:29])[C@H:22]2[CH2:30][CH3:31])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COCC1Cc2c(C(=O)O)ccc(N)c2O1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(COC)C4)nc2N1C1CCCC1
Yield: 44.5 %

Procedure:
7-Amino-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 40d (160 mg, 0.70 mmol) and (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydro-5H-pteridin-6-one 1o (232 mg, 0.80 mmol) were dissolved in 34 mL of the mixture solvent of ethanol and water (V:V=1:2.4) followed by the addition of 0.4 mL of concentrated hydrochloric acid. The reaction solution was heated to reflux for 16 hours with stirring, then cooled down resulting in the formation of precipitate. The precipitate was filtered to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid 40e (0.15 g, yield: 43.0%) as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH2:22]=O>[Ni].CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH2:13][N:12]([CH3:22])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: C=O
Reactant: COc1ccc2c(c1)CNCC2c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)CN(C)CC2c1ccc(Cl)c(Cl)c1

Procedure:
The free base prepared from 5.20 g. of rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride is stirred at room temperature with 75 ml. of methanol and 3.8 ml. of 35% formaldehyde solution for 2 hours and thereupon hydrogenated over 2 g. of Raney nickel. After filtering off, evaporation, acidification with ethanolic hydrogen chloride, crystallization and recrystallization from methanol-ether, there is obtained rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride, m.p. 273°-275°.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH:19][C:20]1([C:33]#[C:34][CH2:35][O:36][Si](C)(C)C)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1>O1CCCC1>[OH:19][C:20]1([C:33]#[C:34][CH2:35][OH:36])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#CCO[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C#CCO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
Tetrabutylammonium fluoride (1M in tetrahydrofuran, 80 ml, 80 mmol) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-trimethylsilyloxypropynyl)-1-piperidinecarboxylate (from step (i) above; 24.4 g, 75 mmol) in tetrahydrofuran (300 ml) and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and water (200 ml) was added. The mixture was extracted with ethyl acetate (2×200 ml) and the combined organic fractions were washed with water (2×200 ml) and brine (200 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as an orange oil (16.8 g, 88%).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:34]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[C:13]=12>ClCCl>[O:27]([C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([CH:34]3[CH2:38][CH2:37][NH:36][CH2:35]3)[N:19]=2)=[CH:26][CH:25]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 8 mL) was added to a solution of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinecarboxylate (240 mg, 0.508 mmol) in dichloromethane (1 mL) at 0° C. After 15 minutes, the ice-bath was removed and the reaction mixture was stirred at room temperature for 5 hours. Solvents were then evaporated and the residue was dissolved in ethyl acetate. Saturated sodium bicarbonate was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated give 3-(4-phenoxyphenyl)-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.157 mg, 91%). 1H NMR (DMSO-d6) δ 1.99-2.21 (m, 2H), 2.94 (m, 1H), 3.04-3.23 (m, 3H), 5.31 (m, 1H), 7.14 (m, 5H), 7.44 (m, 2H), 7.67 (m, 2H), 8.24 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].Cl.[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][Cl:28])[CH3:24]>>[ClH:28].[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:24]
Reactant: CCN(CC)CCCl
Reactant: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Product: CCN(CC)CCn1c(=Nc2ccc(C)cc2)sc2ncccc2c1=O
Yield: 41.1 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.34 mmol) of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 54 mg of lithium hydride and 633 mg of 2-diethylaminoethylchloride hydrochloride were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform-3% methanol). The resulting compound was then recrystallized from a mixture of ether and hexane containing 4 N hydrogen hydride in dioxane to obtain 556 mg of 3-(2-diethylaminoethyl)-2,3-dihydro-2-[(4-methylphenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one monohydrochloride.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH2:8]1[CH:12]2[CH2:13][C:14](=[O:16])[CH2:15][CH:11]2[CH2:10][NH:9]1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>C(#N)C>[C:3]([N:9]1[CH2:10][CH:11]2[CH2:15][C:14](=[O:16])[CH2:13][CH:12]2[CH2:8]1)(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1CC2CNCC2C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CC2CC(=O)CC2C1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f (717 mg, 3 mmol) was dissolved in 20 mL of acetonitrile followed by addition of di-tert-butyl dicarbonate (0.42 mL, 4.5 mmol) and triethylamine (0.98 mL, 9 mmol) upon cooling by an ice-water bath. The reaction mixture was stirred overnight at the same temperature. The mixture was concentrated and diluted with 50 mL of water. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-acetyl-hexahydro-cyclopenta[c]pyrrol-5-one 5a (0.36 g, yield 72%) as a colorless oil
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:26])([F:25])[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1>C(Cl)Cl>[F:26][C:9]([F:8])([F:25])[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Trifluoroacetic acid (1.15 mL) was added dropwise to a solution of tert-butyl 4-(2,2,2-trifluoroethoxy)piperidine-1-carboxylate (prepared in an analogous manner to Intermediate 203, 1.14 g, 4.0 mmol) in DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated under vacuum, the crude residue was dissolved in water and product was extracted with diethylether (2 times). The aqueous phase was basicified to pH 10 using solid potassium carbonate and extracted with DCM (4 times). The organic extracts were combined, dried over sodium sulfate and concentrated under vacuum to afford the title compound (610 mg, 83%). 1H NMR (300 MHz, CDCl3) δ ppm 3.84 (2H, q), 3.53 (1H, m), 3.10 (2H, m), 2.61 (2H, m), 1.76 (2H, m) and 1.54 (2H, s).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[BH4-].[Na+].O>CO>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)=[CH:11][CH:10]=1
Reactant: O=Cc1ncc[nH]1
Reactant: Nc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Clc1ccc(NCc2ncc[nH]2)cc1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
The solution of 2-imidazolecarboxaldehyde (570 mg, 5.9 mmol) and 4-chloroaniline (756 mg, 5.9 mmol) in methanol (5 ml) was stirred at 60° C. for 4 hours, and allowed to cool to room temperature. To the reaction was added NaBH4 (337 mg, 8.9 mmol), and the mixture was additionally stirred for an hour. Water (20 mL) was added to the reaction, which was extracted with ethyl acetate (50 mL). Organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol in chloroform) to give the title compound (660 mg, 53%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:35])[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(-c4ccccc4)cc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(-c4ccccc4)cc3)c2c1
Yield: 105.1 %

Procedure:
480 mg of 2-[4-(biphenyl-4-ylamino)-quinazolin-6-ylcarbamoyl]-ethyl-carbamic acid t-butylester (prepared in accordance with the procedure of Example 80) dissolved in 10 ml of methylene chloride was reacted with 10 ml of trifluoroacetic acid at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 50 ml of saturated aqueous sodium bicarbonate for 30 mins, filtered under a reduced pressure, and dried to obtain the title compound (400 mg, 99%).
Reaction SMILES: [N+:1]([C:4]1[C:12]([N+:13]([O-])=O)=[CH:11][C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>CCO.[Pd]>[NH2:13][C:12]1[C:4]([NH2:1])=[CH:5][C:6]2[NH:10][CH:9]=[N:8][C:7]=2[CH:11]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc2nc[nH]c2cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2nc[nH]c2cc1N
Yield: 67.5 %

Procedure:
The product obtained in Step 1 (2.5 g, 12 mmol) and Pd/C (0.5 g) were dissolved in EtOH (50 mL), reacted in a Parr hydrogenation apparatus at room temperature and hydrogen gas pressure until the reaction is completed. The catalyst was removed by filtration, the filtrate was concentrated under vacuum, diluted with ethyl acetate, washed with water, dried, and concentrated under vacuum to obtain a product (1.2 g, 66.7%).