Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[OH:20][CH2:21][C:22]1[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:24]=[CH:25][N:26]=1>>[O:17]1[CH:18]=[CH:19][C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:20][CH2:21][C:22]4[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:24]=[CH:25][N:26]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:16]1
Reactant: C[Si](C)(C)CCOCn1ncnc1CO
Reactant: Clc1nn2c(-c3ccon3)nnc2c2ccccc12
Product: C[Si](C)(C)CCOCn1ncnc1COc1nn2c(-c3ccon3)nnc2c2ccccc12

Procedure:
The title-compound was prepared from 6-chloro-3-(3-isoxazolyl)-1,2,4-triazolo[3,4-a]phthalazine (described in Example 34, part b) and 3-(hydroxymethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4-triazole (described in Example 45, part c) following the procedure described in Example 45, part d, 1H NMR (360 MHz, CDCl3) δ 0.00 (9H, s, 3 of CH3), 0.88 (2H, q, J=8.4 Hz, CH2), 3.67 (2H; t, J=8.3 Hz, CH2), 5.84 (2H, s, CH2), 5.92 (2H, s, CH2), 7.30 (1H, d, J=1.7 Hz, Ar—H), 7.89 (1H; t, J=7.1 Hz, Ar—H), 7.96 (1H, s, Ar—H), 8.02 (1H, t, J=7.6 Hz, Ar—H), 8.32 (1H, d, J=8.2 Hz, Ar—H), 8.70 (1H, s, Ar—H), 8.75 (1H, d, J=8.2 Hz, Ar—H).
Reaction SMILES: [N:1]1([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5]CCN1.I[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.[CH2:36]([N:38](CC)CC)[CH3:37].C(=O)(O)[O-].[Na+]>C1COCC1>[C:30]1([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][N:38]3[CH2:5][CH2:6][CH2:7][N:1]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=4)[CH2:37][CH2:36]3)=[CH:24][CH:25]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: ICCOc1ccc(Cc2ccccc2)cc1
Reactant: COC(=O)c1ccc(CN2CCCCCN2)cc1
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2CCCN(CCOc3ccc(Cc4ccccc4)cc3)CC2)cc1
Yield: 27.3 %

Procedure:
A mixture of methyl 4-[(hexahydro-1H-diazepin-1-yl)methyl]benzoate (109 mg, 0.44 mmol) and 1-(2-iodoethoxy)-4-(benzyl)benzene (120 mg, 0.44 mmol) in THF (4 mL) was treated with triethylamine (112 μl, 0.80 mmol) and heated at reflux for 5 hours. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 55 mg of methyl 4-[[hexahydro-4-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-1,4-diazepin-1-yl]methyl]benzoate; 1H NMR (300 MHz, CDCl3) δ 7.98 (d, 2H), 7.42 (d, 2H), 7.28 (dd, 2H), 7.17 (d, 2H), 7.18 (dd, 1H), 7.09 (d, 2H), 6.82 (d, 2H), 4.05 (t, 2H), 3.92 (s, 2H), 3.91 (s, 3H), 3.69 (s, 2H), 2.97 (t, 2H), 2.88 (m, 2H), 2.84 (m, 2H), 2.69 (m, 4H), 1.81 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C[O:28][B:29](OC)[O:30]C>C1COCC1>[CH3:19][C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:4]2[CH:3]=[C:2]([B:29]([OH:30])[OH:28])[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])[CH3:20]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Br)c2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3-bromophenyl)methyl]-1-piperazinecarboxylate (6.55 g) in THF (20 mL) at −70° C. was added dropwise n-butyl lithium (15.4 mL, 2.5M solution in hexanes) over 10 minutes. After stirring for 30 mins at that temperature, the resulting orange solution was treated with trimethylborate (8.02 g). The reaction mixture was then allowed to warm up to room temperature and quenched with saturated ammonium chloride (15 mL). The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase was separated and further extracted with ethyl acetate (20 mL). The organic phases were combined, dried (MgSO4) and evaporated under vacuum to give the title compound (5 g) which was used directly for the preparation of 1,1-dimethylethyl 4-[(3′-cyano-3-biphenylyl)methyl]-1-piperazinecarboxylate without further purification. LC/MS: m/z, 321 (M+H), 1.91 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:20][C:21]#[N:22].[K+].OP(O)(O)=O>O.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:21]([NH2:22])=[O:20])[CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C[O-]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(N)c1
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(NC(N)=O)c1

Procedure:
A solution of α-t-butoxycarbonylamino-m-aminophenylacetic acid (2.66 g, 0.01 mol) and potassium cyanate (0.81 g, 0.01 mol) in a mixture of water (35 ml) and acetic acid (2.5 ml) was heated at 56° for 3 hours. The solution was cooled, acidified with 40% H3PO4, and extracted with ethyl acetate. The dried extracts were evaporated to give the title product: mp 93°-95° (dec).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[C:24]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=O)=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1>CN(C)C=O.C(O)(=O)C>[Cl:22][C:23]1[C:24]([C:29]2[CH:37]=[CH:36][C:32]([C:33]3[NH:10][C:5]4[CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=[CH:7][C:6]=4[N:9]=3)=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, 1.0 mL (5.0 mmol) diisopropylethylamine and 1.1 g (6 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyleuronium hexafluorophosphate were added to a solution of 0.59 g (2.5 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 25 mL dimethylformamide, which was then stirred for 5 min, irradiated for 15 min with microwaves in a microwave reactor (Initiator Sixty, Biotage) and concentrated in a vacuum. The concentrate was dissolved in ethyl acetate, washed with saturated NaHCO3 and saturated NaCl, and dried over magnesium sulfate, followed by vacuum concentration. The residue thus obtained was dissolved in acetic acid (15 mL) and stirred for 5 min before irradiation for 15 min with microwaves in a microwave reactor (Initiator Sixty, Biotage). Again, the reaction solution was cooled to room temperature, vacuum concentrated, dissolved in ethyl acetate, washed with saturated NaHCO3 and saturated NaCl, and dried over magnesium sulfate, followed by vacuum concentration. The residue was separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.81 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 90%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([CH3:20])[C:8]=1[C:9]([OH:11])=O.C1(C)C=CC=CC=1.[Cu][C:29]#[N:30]>C(#N)C>[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([CH3:20])[C:8]=1[C:9]([C:29]#[N:30])=[O:11]
Reactant: N#C[Cu]
Reactant: COc1cc(C)c(C(=O)O)c(OC)c1OC
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc(C)c(C(=O)C#N)c(OC)c1OC
Temperature: 25 °C
Yield: 44.7 %

Procedure:
10 ml of thionyl chloride was added to 6.0 g (26.6 mmol) of 2,3,4-trimethoxy-6-methylbenzoic acid, followed by stirring under reflux with heating for 4 hours, and the surplus thionyl chloride was distilled off under reduced pressure. 20 ml of toluene, 8 ml of acetonitrile and 3.1 g (34.5 mmol) of copper(I) cyanide were added, followed by stirring under reflux with heating for 16 hours. After cooling to room temperature, the reaction solution was subjected to filtration on the pad of celite, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 2.8 g (yield: 45%) of 2,3,4-trimethoxy-6-methylbenzoyl cyanide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[C:7]=1[OH:16])=[O:5])C.[H-].[Na+].[CH3:19]I>O1CCCC1>[CH3:1][O:3][C:4]([C:6]1[S:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[C:7]=1[O:16][CH3:19])=[O:5]
Reactant: CCOC(=O)c1sc2ncnc(Cl)c2c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sc2ncnc(Cl)c2c1OC
Reaction time: 1 h

Procedure:
4-Chloro-5-hydroxy-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.4 g, 1.5 mmol) in tetrahydrofuran (10 mL) was slowly added to a slurry of sodium hydride (60 percent in mineral oil, 0.1 g 2.5 mmol) in tetrahydrofuran (30 mL) and stirred for one hour. Methyl iodide (2 mL) was added and the solution warmed to reflux for two hours. After cooling the reaction was quenched with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine, dried (NaSO4) and concentrated. The residue was purified by chromatography over silica (40 percent ethyl acetate/hexane) affording product as a yellow solid. (0.2 g, 50 percent) yield.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4]O.S(Cl)([Cl:13])=O>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C)c1CO
Product: Cc1cccc(C)c1CCl
Reaction time: 6 h

Procedure:
To a stirred solution of 2,6-Dimethylbenzyl alcohol (9.94 g, 73 mmol) was added thionyl chloride (81.55 g, 685 mmol) at room temperature. The reaction mixture was stirred for 6 hours, concentrated under reduced pressure and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:50]([O:52][CH2:53][CH3:54])=[O:51]>CN(C=O)C>[CH2:53]([O:52][C:50]([N:22]1[CH2:21][CH2:20][CH:19]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][C:9]([NH:8][C:5]4[N:4]=[C:3]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:2]([Cl:1])=[CH:7][N:6]=4)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:11]=3)[C:15]2=[O:18])[CH2:24][CH2:23]1)=[O:51])[CH3:54]
Reactant: CCOC(=O)Cl
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(N2Cc3cc(OC(C)C)c(Nc4ncc(Cl)c(Nc5ccccc5S(=O)(=O)C(C)C)n4)cc3C2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 15 mg, 0.025 mmol) and triethylamine (37.5 uL, 0.25 mmol) in DMF (0.5 mL), is added ethyl chloroformate (5.4 mg, 0.05 mmol). The mixture is stirred at room temperature for 1 hour. The crude reaction mixture is purified by mass-trigger preparative RP LC-MS to afford the title compound 4-(6-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid ethyl ester (175) as a white solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.55 (d, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.82 (dd, 1H), 7.74 (t, 1H), 7.34 (t, 1H), 7.28 (s, 1H), 4.73 (m, 2H), 4.39 (s, 2H), 4.12 (m, 2H), 4.06 (q, 2H), 3.46 (m, 1H), 2.92 (m, 2H), 1.76 (m, 2H), 1.68 (m, 2H), 1.29 (d, 6H), 1.20 (t, 3H), 1.17 (d, 6H); MS m/z 671 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[C:10]([C:14](=[N:17][OH:18])[C:15]#[N:16])=[N:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1.C([N:21](CC)CC)C.NO>O1CCOCC1.CO>[Br:1][C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[C:10]([C:14]3[C:15]([NH2:21])=[N:16][O:18][N:17]=3)=[N:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CCn1c(C(C#N)=NO)nc2c(Cl)ncc(Br)c21
Agent: NO
Solvent: CO
Solvent: C1COCCO1
Product: CCn1c(-c2nonc2N)nc2c(Cl)ncc(Br)c21
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a mixture of (7-bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)hydroxyimino-acetonitrile (V, 545 g, 1.45 mol) in dioxane (5 L) was added triethylamine (1 L) and hydroxylamine (143 g, 55% in water). The reaction was heated at reflux for 6 h. After cooling the reaction to ambient temperature, the mixture was filtered and the filtrate concentrated under reduced pressure to give a brown solid. The solid was suspended in methanol (1 L) and the suspension was stirred at 65° C. for 0.5 h. The solid was collected by filtration and dried to give 321 g (70% yield) of the desired compound (VI). This was used in the next step without further purification. MS (ES+) m/z 343 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: Cc1ccc(CC(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4-methylphenylacetic acid (1.50 g, 10.0 mmol) in dried dichloromethane was added nitric acid (fuming, 1.5 mL) dropwise. The mixture was stirred at room temperature for 2 hours, then quenched with water and extracted with ethyl acetate. The extracts were washed with water twice and brine, dried over magnesium sulfate, filtered, and concentrated to provide the title compound (1.66 g, 85% yield): 1H NMR (CDCl3) 7.91 (d, 1H), 7.42 (dd, 1H), 7.31 (d, 1H), 3.71 (s, 2H), 2.58 (s, 3H); ES-MS m/z 196 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClCc1ccccn1
Reactant: O=c1[nH]ncc2ccc([N+](=O)[O-])cc12
Agent: Cl
Product: O=c1c2cc([N+](=O)[O-])ccc2cnn1Cc1ccccn1

Procedure:
Step (b) of Example 125 was repeated, except that the compound prepared in step (b) of Example 137 and 2-(chloromethyl)pyridine hydrochloride were used as the starting compounds. Thus, 7-nitro-2-(pyridin-2-yl)methyl-2H-phthalazin-1-one was obtained.
Reaction SMILES: C(O[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH2:20][C:21]#[N:22]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH2:20][C:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH2:20][CH:21]([NH2:22])[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: N#CCc1cc(F)ccc1F
Product: NC(Cc1cc(F)ccc1F)c1cccnc1
Product: O=C(Cc1cc(F)ccc1F)c1cccnc1

Procedure:
The title compound was generated from commercially available nicotinic acid ethyl ester and (2,5-difluoro-phenyl)-acetonitrile according to the general procedure D described above. The intermediates 2-(2,5-difluoro-phenyl)-1-pyridin-3-yl-ethanone and 2-(2,5-difluoro-phenyl)-1-pyridin-3-yl-ethylamine were isolated and characterized.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.C(O[C:34]1(O[Si](C)(C)C)[CH2:36][CH2:35]1)C.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[ClH:27].[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:14]3[C:13](=[O:28])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH:3]5[CH2:4][N:1]([CH:34]6[CH2:36][CH2:35]6)[CH2:2]5)=[C:7]([O:29][CH3:30])[CH:8]=4)[CH2:17][CH2:16][C:15]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C2CC2)C1
Product: Cl
Temperature: 25 °C
Yield: 64 %

Procedure:
Mix molecular sieves (60 mg, type 3A), 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (1.00 g, 2.26 mmoles), [(1-ethoxycyclopropyl)oxy]trimethylsilane (685.2 μL, 3.39 mmoles), and acetic acid (648 μL, 11.31 mmoles) in dry methanol (11.4 mL). Reflux the mixture for 3 h. Cool the mixture to room temperature, add sodium cyanoborohydride (300 mg, 4.53 mmol) and slowly warm to 40° C. for 1 h. Cool the mixture and add 1 N NaOH solution. Extract the aqueous layer with CHCl3 (3×25 mL). Purify on HPLC, 4.6×150 mm Kromasil® silica, Eluent: 40% THF/heptane 0.1% N,N′-dimethylethylamine, 1 mL/min. Re-dissolve the material in CHCl3 and add 1 N HCl/Et2O solution (750 μL). Concentrate the solvent in vacuo to give 375 mg (34%) of the title compound. ES/MS m/z (35Cl) 482.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[O:30])=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([O:34]CC)=[O:33])=[N:10]2)=[CH:5][CH:4]=1.[OH-].[Li+].CO.Cl>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:31])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]5=[O:30])=[CH:22][CH:23]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:32]([OH:34])=[O:33])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(-n3ccccc3=O)cc1)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-n2nc(C(=O)O)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Yield: 78.7 %

Procedure:
Ethyl 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1(2H)-pyridinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (0.5 g, 1.03 mmol) was hydrolyzed with lithium hydroxide (0.13 g, 3 mmol) and a mixture of methyl alcohol (5 mL), THF (25 mL) and water (25 mL) for 24 h. The reaction was acidified with conc. HCl and the resulting solid filtered off. The product was suspended in 1:1 CH2Cl2/hexanes, filtered, and dried to afford 0.37 g (79%) white solid; Mass Spec (M+H)+ 457.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:23][CH:24]([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([Cl:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[ClH:35].[F:36][CH:24]([F:23])[O:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:20][C:18]2[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: COc1ccc(N)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc(OC(F)F)cc2)cc1N1CCNCC1
Product: Cl

Procedure:
The compound was prepared as described for Example 1 by reaction of 4-(5-amino-2-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester with commercially available 4-difluoromethoxy benzene sulfonylchloride followed by deprotection.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:16]O>S(=O)(=O)(O)O>[CH3:16][O:12][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:14])([F:1])[F:15])[CH:5]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(SC(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(SC(F)(F)F)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-(trifluoromethylthio)phenylacetic acid (5.00 g, 21.17 mmol) in methanol (50 mL) was treated slowly with 10 drops of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (100 mL). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford (3-trifluoromethylsulfanyl-phenyl)-acetic acid methyl ester (5.28 g, 99%) as a pale yellow oil which was used without further purification: EI-HRMS m/e calcd for C10H9F3O2S (M+) 250.0275, found 250.0274.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:42])([F:41])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[N:26]=[C:25]([N:27]3[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[N:28]3)[CH:24]=[CH:23][CH:22]=2)=[C:9]([CH:43]=O)[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:41])([F:42])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[N:26]=[C:25]([N:27]3[C:31]([C:32]([F:33])([F:35])[F:34])=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[N:28]3)[CH:24]=[CH:23][CH:22]=2)=[C:9]([CH:43]=[CH2:2])[CH:8]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OC(F)(F)c3ccc(Br)cc3C=O)n2)c1C(F)(F)F
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(Br)ccc1C(F)(F)Oc1ccccc1-c1cccc(-n2ncc(C(=O)OCC)c2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a cooled (0° C.) suspension of methyltriphenyl phosphonium bromide (5.33 g, 14.9 mmol) in THF (100 mL) was added dropwise n-BuLi (5.5 mL, 2.5 M in hexanes, 13.8 mmol). After aging for 40 min, the reaction mixture was allowed to warm up to ambient temperature for 25 min, at which point 7.4 mL of the supernatant was taken and added to the title compound from Example 302 Step D (270 mg, 0.442 mmol). After 30 min, the mixture was quenched by addition of water and the aqueous phase was extracted with hexane-EtOAc. The organic phase was separated and concentrated in vacuo. Purification by silica gel flash chromatography (5% to 15% EtOAc in hexanes) provided the title compound: LCMS m/z 590.5 [M−F]+; 1H NMR (500 MHz, CD2Cl2) δ 8.13 (s, 1H), 7.86 (m, 2H), 7.77 (m, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.55-7.48 (m, 2H), 7.45-7.40 (m, 3H), 7.08 (m, 1H), 5.68 (d, J=17.2 Hz, 1H), 5.32 (d, J=11.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:4][CH:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:6]1)(=O)C.O=CC(Cl)(Cl)Cl.C(N(CC)CC)C.C(C(C)=O)C(C)C>O>[OH:4][CH:5]1[CH2:9][C:8](=[O:10])[C:7]([CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:6]1
Reactant: COC(=O)CCC#CCCC1=CC(OC(C)=O)CC1=O
Agent: O=CC(Cl)(Cl)Cl
Solvent: CC(=O)CC(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCC#CCCC1=CC(O)CC1=O
Yield: 86 %

Procedure:
A mixture (9.45 g) of the compound [IX-1] and the racemic 4-hydroxycyclopentenone obtained in Example 7, chloral (0.24 g) and triethylamine (0.43 g) is reacted at 60° C. for 5 hours. After completion of the reaction, to the mixture are added methyl isobutyl ketone (30 ml) and water (20 ml). The organic layer is separated and washed successively with 1% aqueous hydrochloric acid solution and water, and methyl isobutyl ketone is distilled off therefrom to give 4-hydroxy-2-(6-methoxycarbonyl-3-hexynyl)-2-cyclopentenone (racemic 4-hydroxycyclopentenone) (8.13 g, yield; 86%).