Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCCC(C(=O)OC)c1c(C)nc(Nc2ccccc2)nc1-c1ccc(C)cc1
Yield: 49.6 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), aniline (0.033 mL; 0.361 mmol), palladium acetate (2 mg, 0.009 mmol) and xantphos (10 mg; 0.018 mmol) were placed in a 2 mL reaction tube and dissolved in dioxane (1 mL), the tube was purged with argon, sealed and irradiated in a microwave oven at 160° C. for 15 min. The reaction mixture was partitioned between a saturated sodium chloride solution and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to yield 58 mg (39%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:9][O:10][C:11](=[O:24])[CH:12](O)[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:9][O:10][C:11](=[O:24])[CH:12]([O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=1)[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1
Reactant: COC(=O)C(O)Cc1c[nH]c2ccccc12
Reactant: Oc1cncc(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)C(Cc1c[nH]c2ccccc12)Oc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
A 100 mL RBF was charged with 3-bromo-5-hydroxypyridine (1.67 g, 9.58 mmol), 2-hydroxy-3-(1H-indol-3-yl)-propionic acid methyl ester (2.1 g, 9.58 mmol) which was synthesized according to literature method (M. E. Jung et al J. Org. Chem. 1999, 64, 2976) and Ph3P (3.01 g, 11.5 mmol), and was purged with nitrogen. THF (40 mL) was added at 0° C. After stirring at 0° C. for 10 min, DEAD (1.81 mL, 11.5 mmol) was added via syringe. The reaction mixture was stirred at 0° C. for 1 h and at rt overnight. The reaction mixture was concentrated and the residue was separated by flash chromatography (20-60% EtOAc in hexane) to provide the desired product (3.4 g, 94%). MS (DCI) m/z 375, 377 (M+1)+.
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)[CH2:2]CCC.[F-].O.O.O.[C:22]1([CH3:29])[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1.O>CS(C)=O>[CH2:26]([C:27]1[CH2:22][CH:29]=1)[CH2:25][CH2:24][CH2:23][CH2:28][CH3:2]
Reactant: Cc1ccccc1C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCC1=CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In situ, 0.586 g (2.0 mmol) of (trans)-1-hexyl-1-(methane sulfonyloxy)-2-(trimethylsilyl)cyclopropane of Preparation Example 9 was dissolved in 2.0 ml of DMSO, 0.94 g of Bu4NF.3H2O was added thereto and the resulting mixture was vigorously stirred at room temperature for one hour. 8.0 ml of xylene and 5.0 ml of water were added to the reaction solution and vigorously stirred for 5 minutes and stood. When the mixture was separated into a xylene layer (upper layer) and an aqueous layer (lower layer), only the xylene layer was collected and the aqueous layer was discarded. 1.0 g of sodium dodecylbenzenesulfonate and 1.0 g of tristyrenylphenykethoxy)12ethanol were added to the xylene layer, stirred for 5 minutes, 2.0 L of water was added thereto and the resulting mixture was slowly stirred such that it was homogeneously mixed. As a result, a 1.0 mM 1-hexylcyclopropene formulation was prepared. This solution was diluted to 1 to 100 times prior to use, as necessary.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:55])([CH3:54])[CH2:11][N:12]1[CH:21]=[C:20]([S:22]([N:25]2[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)(=[O:24])=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:39]3[CH:44]=[C:43]([C:45](=[O:50])[NH:46][CH:47]4[CH2:49][CH2:48]4)[CH:42]=[C:41]([F:51])[C:40]=3[CH3:52])[CH:18]=2)[C:13]1=[O:53])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:47]1([NH:46][C:45](=[O:50])[C:43]2[CH:42]=[C:41]([F:51])[C:40]([CH3:52])=[C:39]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:53])[N:12]([CH2:11][C:10]([CH3:55])([CH3:54])[CH2:9][OH:8])[CH:21]=[C:20]4[S:22]([N:25]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[CH:44]=2)[CH2:49][CH2:48]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)(=O)N3CCCNCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
To a solution of tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfonyl)-1,4-diazepane-1-carboxylate (Example 46d, 0.055 g) in DCM (4 mL) was added trifluoroacetic acid (1 mL), and the reaction was stirred at room temperature overnight. Toluene (6 mL) was added and the volatiles removed in vacuo (repeated 3 times). The residue was dissolved in methanol and purified by SCX, flushing with methanol (impurities), and eluting the product with 0.7 N methanolic ammonia. Purification by preparative HPLC (Phenomenex Gemini column using a 95-5% gradient of 0.2% aqueous trifluoroacetic acid in acetonitrile as eluent), evaporation of solvents and trituration with diethyl ether gave the title compound (0.011 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([OH:11])[CH2:9][CH2:8][S:7][CH2:6]1)=[O:4].[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13].N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([O:11][C:12]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[S:13])[CH2:9][CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@@H]1CSCC[C@@H]1O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CSCC[C@@H]1OC(=S)n1ccnc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 55.5 %

Procedure:
A solution of 4(S)-hydroxy-tetrahydro-thiopyran-3(R)-carboxylic acid methyl ester (1.00 g, 5.674 mmol) in dry tetrahydrofuran (50 mL), under argon, was treated with 1,1′-thiocarbonyldiimidazole (2.085 g, 11.35 mmol) and pyridine (6.88 μL, 8.511 mmol). The reaction mixture was stirred at 25° C. for 36 h and was then diluted with ethyl acetate (100 mL). The resulting solution was washed sequentially with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 4(S)-(imidazole-1-carbothioyloxy)-tetrahydro-thiopyran-3(R)-carboxylic acid methyl ester (901 mg, 55.4%) as a beige oil: EI-HRMS m/e calcd for C11H14N2O3S2 (M+) 286.0446, found 286.0438.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@:9]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:12][CH:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([Mg]Br)[CH2:28][CH:29]=[CH2:30]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C@:9]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:12][CH:13]([OH:14])[CH2:30][CH2:29][CH:28]=[CH2:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCC[Mg]Br
Reactant: CCOC(=O)[C@@]1(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1CC=O
Solvent: C1CCOC1
Product: C=CCCC(O)C[C@@H]1C[C@@]1(C(=O)OCC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To a solution of (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(2-hydroxyethyl)cyclopropanecarboxylate (8.65 g, 23.2 mmol) in dichloromethane (116 ml) at 25° C. was added Dess-Martin Periodinane (13.8 g, 32.4 mmol). The mixture was stirred for 3 h and quenched with 1 N sodium thiosulfate (70 mL) and aqueous saturated sodium bicarbonate solution (30 mL), and stirred for 1 h. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. This material was purified by flash chromatography on silica gel (eluted with 25% ethyl acetate/hexane) to yield (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(2-oxoethyl)cyclopropanecarboxylate (7.05 g, 82% yield) as an oil. MS (ESI): m/z=394.1 [M+Na]. To (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(2-oxoethyl)cyclopropanecarboxylate (7.05 g, 19.0 mmol) in tetrahydrofuran (60 mL) at −78° C. was added but-3-enylmagnesium bromide (45.6 mL, 22.78 mmol) and the reaction mixture was stirred for 30 min. The mixture was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residual oil was purified via flash chromatography on silica gel (25% hexane/ethyl acetate) to provide the title compound (2.75 g, 34%) as an oil, along with recovered starting material (2.89 g, 41%). MS (ESI): m/z=450.1 [M+Na].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]([NH2:29])=O)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].N1C(Cl)=NC(Cl)=NC=1Cl.O.C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=2)[NH:15][C:14]([C:27]#[N:29])=[CH:13]3)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C#N)cc3c2)cc1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
5-[4-(Methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-ylmethoxy)-1H-indole-2-carboxamide (250 mg) was dissolved in N,N-dimethylformamide (5 mL), cyanuric chloride (311 mg) was added under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=10:90-60:40, volume ratio) to give the title compound (240 mg, yield 100%) as a white solid. MS 445 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>[Zn]>[C:11]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10])(=[O:13])[CH3:12]
Reactant: COc1ccc(Cl)cc1N
Reactant: CC(=O)OC(C)=O
Agent: [Zn]
Product: COc1ccc(Cl)cc1NC(C)=O

Procedure:
0.2 mol (31.5 g) of 2-amino-4-chloroanisole, 40 ml of absolute alcohol, 20 ml of acetic anhydride and a pinch of zinc powder are placed in a 150 ml flask; the solution is brought to reflux for 30 minutes. The reaction liquid is poured onto crushed ice. The product obtained is separated; it is crystallized in a methanol/water mixture (20/80).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7]2[CH:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[CH3:11].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:35]([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:36][CH2:37][CH2:38][CH3:39].N12CCCN=C1CCCCC2.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7]2[CH:15]=[C:14]([C:16](=[O:17])[NH:43][S:40]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[CH3:11]
Reactant: CCCCCS(N)(=O)=O
Reactant: Cc1sc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
3-(3,4-Dichlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic acid (160 mg) was dissolved in dry dimethylformamide (2 ml). Carbonyl-diimidazole (111 mg) was added and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added n-pentanesulfonamide (108 mg) and 1,8-diazabicyclo[5,4,0]undec-7-ene (122 mg) and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was cooled in ice, and the pH thereof was adjusted to pH 4 with 1N hydrochloric acid. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was eluted by silica gel column chromatography (hexane:ethyl acetate=1:1). The resulting residue was crystallized from hexane-ethyl acetate to give 3-(3,4-dichlorobenzyl)-2-methyl-5-(n-pentanesulfonyl-carbamoyl)benzo[b]thiophene (118 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:14][C:6]2=[C:7]([CH3:13])[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[CH2:4][O:3]1.[C:16]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(Cl)CCl.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:12][CH2:11][C:10]2[CH:9]=[N:8][C:7]([CH3:13])=[C:6]3[O:14][C:2]([CH3:15])([CH3:1])[O:3][CH2:4][C:5]=23)=[O:25])=[CH:27][CH:28]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1ncc(CN)c2c1OC(C)(C)OC2
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ncc(CNC(=O)c2ccc(C(C)(C)C)cc2)c2c1OC(C)(C)OC2
Yield: 86.3 %

Procedure:
A mixture of C-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)-methylamine (1.77 g, 8.49 mmol), 4-tert-butylbenzoic acid (5.6 g, 31 mmol), EDC (5.7 g, 29 mmol), and DMAP (4.53 g, 35.6 mmol) was stirred in dichloromethane (200 mL) for 24 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the dichloromethane layer was separated. The aqueous layer was then extracted with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The crude mixture was purified by column chromatography on silica gel using a gradient mixture of dichloromethane:acetone (1:0 to 7:3) as eluant to give 4-tert-butyl-N-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl-methyl)-benzamide (74) (2.7 g, 85%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:53])[C:31]4[C:36]([C:37]=3[C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]5OC(C)(C)C(C)(C)[O:45]5)[CH:39]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:12]=3)[C:3]=12.Cl.C(Cl)Cl.O>CC#N>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:53])[C:31]4[C:36]([C:37]=3[C:38]3[CH:39]=[C:40]([CH:41]=[CH:42][CH:43]=3)[CH:44]=[O:45])=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:12]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1cccc(C2OC(C)(C)C(C)(C)O2)c1)n1nc(-c2cc(F)cc(OCc3ccccc3)c2)c2c(N)ncnc21
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(C=O)c1)n1nc(-c2cc(F)cc(OCc3ccccc3)c2)c2c(N)ncnc21
Reaction time: 8 h
Yield: 0.1 %

Procedure:
3-(1-(4-amino-3-(3-(benzyloxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1H-isochromen-1-one (intermediate F5, 654 mg, 0,919 mmol) was dissolved in MeCN, then 2M HCl was added and the mixture was stirred overnight. DCM (25 ml) and water (25 ml) were added then phases were separated and the aqueous phase was washed again with 10 ml of DCM. The collected organic phases were concentrated to give the title compound (490 mg, 0.801 mmol, 87% yield) as a brown oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][OH:5].[OH-].[K+].C1C[O:17][CH2:16]C1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C@H:3]2[CH2:4][O:5][C:16](=[O:17])[NH:2]2)[CH:7]=1
Reactant: C1CCOC1
Reactant: N[C@H](CO)c1cccnc1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Solvent: O
Product: O=C1N[C@@H](c2cccnc2)CO1
Temperature: 0 °C
Yield: 23 %

Procedure:
To a solution of (S)-2-amino-2-(pyridin-3-yl)ethanol hydrochloride (0.255 g, 1.46 mmol) in water (2 mL) was added potassium hydroxide (0.573 g, 10.2 mmol) and the reaction stirred until complete dissolution occurred, followed by addition of THF (3 mL) and the reaction cooled to 0° C. To the reaction was next added triphosgene (0.433 g, 1.46 mmol) and the reaction allowed to warm up to ambient temperature and stirred for 18 hours. The reaction was concentrated and the adjusted to about pH 8 with 3N NaOH, and concentrated. The residue was purified on silica gel (2-10% 7N ammonia in MeOH in DCM) to provide (S)-4-(pyridin-3-yl)oxazolidin-2-one (0.054 g, 23% yield) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:24])[C:10](=[N:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C(=O)C)=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:25](=[O:30])(=[O:29])[N:26]([CH3:28])[CH3:27].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:24])[C:10](=[N:13][C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[S:25](=[O:30])(=[O:29])[N:26]([CH3:27])[CH3:28]
Reactant: CC(=O)Oc1ccc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccc(O)cc3)n2C)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1.7 g of 4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(4-acetoxyphenylimino)-3-methyl-4-thiazoline (Example 8) in 30 ml of ethanol and 20 ml of water is brought to pH 11-12 with 2 N caustic soda and stirred at room temperature for 3 hours. After neutralization with 2 N hydrochloric acid, and repeated extraction with methyl acetate, the organic phases are dried, evaporated and the residue recrystallized from ethyl acetate/ethanol. Beige-colored crystals of m.p. 188°-190° C., identical with the product obtained by the method (a)-(c) by thin layer comparison.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[C:8]1([NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14]>CO>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:15][C:4]1[CH2:5][NH:1][C:2](=[O:7])[CH:3]=1
Reactant: O=C1CNC(=O)C1
Reactant: Nc1ccccc1N
Solvent: CO
Product: Nc1ccccc1NC1=CC(=O)NC1

Procedure:
A solution of pyrrolidin-2,4-dione (6.93 g, 70 mmol) produced in step 1 and 1,2-phenylenediamine (7.88 g, 70 mmol) in methanol was stirred at 60° C. for 1 hour. The reaction solution was cooled, and the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%).
Reaction SMILES: COC1C=CC2CCNCCC=2C=1.BrC1C=C(OC)C=CC=1C(C1C=CC(OCCN2CCCCC2)=CC=1)=O.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH2:58][N:59]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]3)=[CH:52][CH:51]=2)=O)=[C:44]([N:65]2[CH2:71][CH2:70][C:69]3[CH:72]=[C:73]([O:76][CH3:77])[CH:74]=[CH:75][C:68]=3[CH2:67][CH2:66]2)[CH:43]=1>>[CH3:77][O:76][C:73]1[CH:74]=[CH:75][C:68]2[CH2:67][CH2:66][N:65]([C:44]3[CH:43]=[C:42]([O:41][CH3:40])[CH:47]=[CH:46][C:45]=3[CH2:48][C:50]3[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH2:58][N:59]4[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]4)=[CH:52][CH:51]=3)[CH2:71][CH2:70][C:69]=2[CH:72]=1
Reactant: COc1ccc2c(c1)CCN(c1cc(OC)ccc1C(=O)c1ccc(OCCN3CCCCC3)cc1)CC2
Agent: COc1ccc(C(=O)c2ccc(OCCN3CCCCC3)cc2)c(Br)c1
Agent: COc1ccc2c(c1)CCNCC2
Product: COc1ccc2c(c1)CCN(c1cc(OC)ccc1Cc1ccc(OCCN3CCCCC3)cc1)CC2
Yield: 83.6 %

Procedure:
Synthesized from 7-methoxy-2,3,4,5-tetrahydro-1H-benz[d]azepine and (2-bromo-4-methoxyphenyl)[4-(2-piperidin-1-ylethoxy)phenyl]methanone according to an analogous synthetic method to Example 116 described below, [4-methoxy-2-(7-methoxy-1,2,4,5-tetrahydrobenz[d]azepin-3-yl)phenyl][4-(2-piperidin-1-ylethoxy)phenyl]methanone (632 mg) was used according to an analogous synthetic method to Example 337 described below to provide 7-methoxy-3-{5-methoxy-2-[4-(2-piperidin-1-ylethoxy)benzyl]phenyl}-2,3,4,5-tetrahydro-1H-benz[d]azepine (514 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 described below to provide the title compound (355 mg).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[N:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]=[CH:27][CH2:26]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([N:25]2[CH2:26][CH:27]=[CH:28][CH2:29][CH2:30]2)[N:3]=1
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)[n+]1[O-]
Reactant: C1=CCNCC1
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reaction time: 1.5 h

Procedure:
24.8 g (70 mmol) of methyl 2-amino-6-[(p-toluenesulfonyl)oxy]-4-pyrimidinecarbamate-3-oxide and 14.5 g (175 mmol) of 1,2,5,6-tetrahydropyridine are boiled at reflux under argon in 400 ml of chloroform. After 90 minutes, the resulting precipitate is filtered off and the chloroform solution is washed with water. The organic phase is separated, dried over sodium sulfate and evaporated under reduced pressure, whereby there is obtained a crystalline solid. A sample of this material is recrystallized from methylene chloride/ether. The thus-obtained methyl 2-amino-6-[3,6-dihydro-1(2H)-pyridyl]-4-pyrimidinecarbamate-3-oxide melts at 221°-223° with decomposition.