Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-:1].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11](I)[CH:12]=1)[C:9](=[O:14])[N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:7]2.COC(=O)[C:27](Cl)([F:29])[F:28]>CN(C=O)C.[Cu]I>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:27]([F:29])([F:1])[F:28])[CH:12]=1)[C:9](=[O:14])[N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:7]2
Reactant: [F-]
Reactant: COc1ccc(CN2Cc3cc(Cl)cc(I)c3C2=O)cc1
Reactant: COC(=O)C(F)(F)Cl
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3cc(Cl)cc(C(F)(F)F)c3C2=O)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
CuI (0.076 g, 0.4 mmol) and potassium fluoride (0.055 g, 0.29 mmol) were added under an N2 atmosphere to a solution 5-chloro-2-(4-methoxy-benzyl)-7-iodo-2,3-dihydro-isoindol-1-one (0.100 g, 0.24 mmol) and chloro-difluoro-acetic acid methyl ester (0.031 mL, 0.29 mmol) in DMF (4 mL). The mixture was stirred at 140° C. for 18 h. The reaction was cooled and the solvent evaporated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-chloro-2-(4-methoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.042 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.79 (s, 3H), 4.25 (s, 2H), 4.72 (s, 2H) 6.86 (d, 2H), 7.25 (d, 2H), 7.56 (s, 1H), 7.73 (s, 1H). GC-MS: m/z 355 (M)+, 334 (M−21)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([Cl:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)=[C:6]([Cl:11])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N=Cc2cccc(Br)c2)c(Cl)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 4-amino-3-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(3-bromo-benzylidene)-amino]-3-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C18H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+]351.9 & 353.9.
Reaction SMILES: C([NH:4][C@@:5]1([C:22](NC(C)(C)C)=[O:23])[CH2:9][CH2:8][O:7][C@@H:6]1[CH2:10][CH2:11][CH2:12][B:13]1[O:17]C(C)(C)C(C)(C)[O:14]1)(=O)C.[OH2:29]>Cl>[NH2:4][C@@:5]1([C:22]([OH:23])=[O:29])[CH2:9][CH2:8][O:7][C@@H:6]1[CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17]
Reactant: O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CCO[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Product: N[C@@]1(C(=O)O)CCO[C@@H]1CCCB(O)O
Temperature: 25 °C

Procedure:
A solution of (2R,3S)-3-acetamido-N-tert-butyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)tetrahydrofuran-3-carboxamide (860 mg) in 6 N HCl (15 mL) was stirred at 90° C. for 1 day. After cooling to room temperature, the reaction mixture was transferred to a reparatory funnel, diluted with deionized water (10 mL) and washed with dichloromethane (3×). The aqueous solution was concentrated. Purification by RP-HPLC (10-100% acetonitrile in water) gave (2R,3S)-3-amino-2-(3-boronopropyl)tetrahydrofuran-3-carboxylic acid, as a white solid (269 mg). 1H NMR (D2O, 300 MHz) δ 3.97 (m, 2 H), 3.82 (m, 1 H), 2.66 (ddd, J1=15 Hz, J2=9.5 Hz, J3=5.5 Hz, 1 H), 2.14 (ddd, J1=15 Hz, J2=9 Hz, J3=6.5 Hz, 1 H), 1.22-1.49 (m, 4 H), 0.67 (m, 2 H); MS (+CI): m/z for C8H16BlNO5: expected 217.1; found 435.3 (2M+H)+, 417.2 (2M+H−H2O)+, 217.7 (M+H)+, 200.0 (M+H−2H2O)+.
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22]C(OC(C)(C)C)=O)[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:32][C:2]([Cl:1])([Cl:33])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methylbutyrylamino)-propionyl]-hexahydropyridazine-3-carboxylic acid 2,2,2-trichloroethyl ester (316 mg, 0.59 mmol) in anhydrous dichloromethane (10 mL) was cooled to 0° C. under a nitrogen atmosphere before adding trimethylsilyl trifluoromethanesulfonate (160 μL, 0.885 mmol). The reaction mixture was stirred at 0° C. for 2 h before adding N,N-diisopropylethylamine (413 μl, 2.36 mmol) to afford (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloroethyl ester. The mixture was evaporated and the residue dissolved with (2R,3R)-3-methoxy-2-methyl-hept-6-enoic acid (162 mg, 0.94 mmol.) in acetonitrile (13 mL) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (250 mg, 1.32 mmol) and 1-hydroxybenzotriazole (220 mg, 1.32 mmol) were added. The reaction was stirred at RT for 15 h then evaporated to give a yellow oil. The oil was purified by silica gel chromatography using ethyl acetate to give the title compound (425 mg, 77%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)=O)[C:5](=[O:16])[N:4]2[C:17]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[NH:18][C:19](=[O:20])[C:3]=12.O.[NH2:27][NH2:28]>C(O)C.C(O)(=O)C.O>[N:27](=[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][N:11]=1)[C:6]1[C:5](=[O:16])[N:4]2[C:17]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[NH:18][C:19](=[O:20])[C:3]2=[C:2]([CH3:1])[CH:7]=1)[NH2:28]
Reactant: NN
Reactant: Cc1cc(C(=O)c2ccncn2)c(=O)n2c1C(=O)NC21CCCCC1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=NN)c2ccncn2)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 8′-methyl-6′-(pyrimidine-4-carbonyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3, 0.7 g, 2.07 mmol) in ethanol (4 mL), acetic acid (4 mL) and water (4 mL) is added hydrazine hydrate (0.13 g, 4.14 mmol). The reaction is stirred at 80° C. overnight. The reaction is cooled to room temperature and concentrated. The crude is resuspended in dichloromethane and is washed with saturated aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude is purified via column chromatography to afford 6′-(hydrazono(pyrimidin-4-yl)methyl)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (4).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])/[C:18](/[CH3:26])=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1>CO.[Pd]>[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])[CH:18]([CH3:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C/C(=C\c1ccccc1)C(=O)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1ccccc1)C(=O)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Yield: 94.1 %

Procedure:
(±)-(E)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-2-methyl-3-phenyl-2-propenamide (0.0144 mol) in methanol (200 ml) was hydrogenated with palladium-on-charcoal 10% (0.52 g) as a catalyst at RT over a 5 hour period under a 1 bar pressure in a Parr apparatus. After uptake of hydrogen, the catalyst was filtered through celite and the solvent was evaporated. The residue was crystallized from 2-butanone/DIPE, yielding 4.9 g (94%) of (±)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-α-methylbenzenepropanamide (compound 164).
Reaction SMILES: [CH2:1]([Li])CCC.[N+:6]([CH3:9])([O-])=O.C([O:14][C:15](=[O:25])[CH2:16][CH:17]([CH2:21][CH:22]([CH3:24])C)[C:18](O)=O)(C)(C)C>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:24]1[CH2:1][CH2:18][C:17]([CH2:9][NH2:6])([CH2:16][C:15]([OH:14])=[O:25])[CH2:21][CH2:22]1
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Reactant: C[N+](=O)[O-]
Reactant: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: NCC1(CC(=O)O)CCCCC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
n-Butyllithium (5.1 mL of a 2.5 M solution in hexanes, 12.75 mmol) was added dropwise to a stirring mixture of nitromethane (0.34 mL, 6.3 mmol) in THF (20 mL) and HMPA (2 mL) at −78° C. under argon. The mixture was allowed to warm to −60° C. and stirred for 1 hour. The mixture was cooled to −78° C. and 3 (0.79 g, 5.73 mmol) was added. The mixture was allowed to warm to −60° C. and stirred for a further 2 hours. The mixture was quenched by addition of saturated ammonium chloride solution (5 mL). After warming to room temperature, dilute hydrochloric acid (10 mL) and ether (30 mL) were added. The organic layer was separated, and the aqueous layer was further extracted with ether (2×25 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the nitro-alcohol 1 (0.50 g, 43%) as a white solid; Rf (heptane/ethyl acetate, 9:1) 0.14; νmax(CH2Cl2)/cm−1 3424 (OH), 1548 (NO2), 1379 (NO2); δH (400 MHz; CDCl3): 4.45 (2H, s, CH2NO2), 3.26 (1H, s, OH), 2.04-1.95 (2H, m), 1.85-1.80 (4H, m), 1.64-1.24 (8H, m).
Reaction SMILES: [CH2:1]([Si:3](Cl)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:9][C:10]1[C@@H:27]([OH:28])[CH2:26][C@:22]2([OH:29])[C:23]([CH3:25])([CH3:24])[C:11]=1[C@@H:12]([OH:47])[C:13]([C@@:15]1([CH3:46])[C@H:20]([C@@H:21]2[O:30][C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:32])[C@:19]2([O:41][C:42]([CH3:44])=[O:43])[CH2:39][O:40][C@@H:18]2[CH2:17][C@@H:16]1[OH:45])=[O:14].[C:48](OC(=O)C)(=[O:50])[CH3:49]>N1C=CC=CC=1>[CH3:2][CH2:1][Si:3]([O:45][C@@H:16]1[C@@:15]2([CH3:46])[C:13]([C@H:12]([O:47][C:48]([CH3:49])=[O:50])[C:11]3[C:23]([CH3:24])([CH3:25])[C@:22]([OH:29])([C@@H:21]([O:30][C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:32])[C@@H:20]2[C@:19]2([O:41][C:42]([CH3:44])=[O:43])[CH2:39][O:40][C@@H:18]2[CH2:17]1)[CH2:26][C@H:27]([OH:28])[C:10]=3[CH3:9])=[O:14])([CH2:6][CH3:7])[CH2:4][CH3:5]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)O[C@H]1C[C@H]2OC[C@@]2(OC(C)=O)[C@H]2[C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C([C@@H](OC(C)=O)C(=O)[C@]12C)C3(C)C
Temperature: 5 °C
Reaction time: 40 h
Yield: 77 %

Procedure:
182 g of triethylsilyl chloride are added over 1 hour 20 minutes to a solution of 293.9 g of 10-deacetylbaccatin III in 2.7 liters of pyridine. The solution obtained is stirred for 40 hours at 5° C. 360 g of acetic anhydride are then added while the temperature is maintained at 5° C. The suspension obtained is stirred for 48 hours at 20° C. and then poured into 40 liters of ice-cold water. The precipitate obtained is separated by filtration, then washed with 8 times 2 liters of water and lastly dissolved in 3 liters of ethyl acetate. The organic phase is dried over magnesium sulphate. After filtration and concentration under reduced pressure, the product obtained is crystallized in isopropyl ether. 7-(Triethylsilyl)baccatin III is thereby obtained in a 77% yield, the characteristics of which product are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1>>[ClH:22].[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:15][C:4]1[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2O)n1
Reactant: COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(COc2cc(Br)cnc2Nc2nc(C)cs2)c1
Product: Cl
Yield: 6.5 %

Procedure:
5-Bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ol (prepared according to Example 3, Step A; 0.100 g, 0.349 mmol), K2CO3 (0.109 g, 0.786 mmol), and 1-(chloromethyl)-3-methoxybenzene (0.070 g, 0.349 mmol) were reacted according to Example 3, Step B, to provide 3-(3-methoxybenzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.010 g, 7.04% yield). 1H NMR (d6-DMSO) δ 7.98 (m, 1H), 7.65 (s, 1H), 7.32 (t, 1H), 7.18 (s, 1H), 7.13 (d, 1H), 6.92 (dd, 1H), 6.66 (s, 1H), 5.27 (s, 2H), 3.77 (s, 3H), 2.25 (s, 3H). Mass spectrum (apci) m/z=406.0 (M+H-HCl).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[Cl:8])=O.[F:10][CH:11]([F:20])[O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>O1CCOCC1>[Cl:8][C:7]1[C:6]([N:16]([C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([O:12][CH:11]([F:10])[F:20])[CH:14]=2)[C:3](=[O:5])[C:2]=1[Cl:1])=[O:9]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Nc1cccc(OC(F)F)c1
Solvent: C1COCCO1
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1cccc(OC(F)F)c1
Yield: 94.8 %

Procedure:
16.7 g (0.1 mole) of 2,3-dichloromaleic anhydride is dissolved in 100 ml of dioxane, and a solution of 15.9 g (0.1 mole) of m-difluoromethoxyaniline in 30 ml of dioxane is added dropwise to it at room temperature over 20 minutes with stirring. Thereafter, the resulting solution is stirred at 70°-80° C. for 2 hours and the dioxane is then distilled off under a reduced pressure. Water is added to the residue to precipitate crystals. The precipitated crystals are filtered off and recrystallized to give 29.2 g (yield: 95%) of 2,3-dichloro-N-(m-difluoromethoxyphenyl)maleimide melting at 122°-124° C. in the form of light yellow plate crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:21][CH2:20][O:19][C:18]2=[C:22]([C:25](O)=[O:26])[S:23][CH:24]=[C:17]12>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:25]([C:22]1[S:23][CH:24]=[C:17]2[C:18]=1[O:19][CH2:20][CH2:21][O:16]2)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Reactant: O=C(O)c1scc2c1OCCO2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)c1scc2c1OCCO2

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with 2,3-Dihydro-thieno[3,4-b][1,4]dioxine-5-carboxylic acid. LC-MS: tR=0.96 min; [M+H]+=381.1.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[CH:6]([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH3:14])[C:4]=2[CH:3]=1.[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH3:24].[C:39](=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:20]2[CH:2]=[CH:3][C:4]3[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:39][C:5]=3[CH:19]=2)=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=C([O-])[O-]
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Reactant: CCCN1CCCCC(C(=O)OC)c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCCN3CCC)cc1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A suspension of methyl 9-bromo-1-propyl-2,3,4,5-tetrahydro-1H-1-benzoazocine-6-carboxylate (2.1 g) and 4-(2-butoxyethoxy)phenyl boric acid (1.84 g), and potassium carbonate (2.14 g) in toluene (25 ml), ethanol (2.5 ml) and water (2.5 ml) was stirred under argon atmosphere for 1 hour and then tetrakis(triphenylphosphine)palladium (343 mg) was added. The mixture was refluxed for 5 hours. After returning to room temperature, water was added and the reaction mixture was and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate=19:1→hexane:ethyl acetate=9:1) to give methyl 9-(4-(2-butoxyethoxy)phenyl)-1-propyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.18 g) as a yellow oily material.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.[N:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[C:37]=[O:38]>CN(C)C=O.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH3:28])=[C:16]([CH:23]4[CH2:24][N:25]([C:37]([NH:36][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])[CH2:26]4)[C:17]([C:18]#[N:19])=[C:20]([Cl:22])[CH:21]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(=O)NC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (20 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL) was treated with triethylamine (20 μL, 0.14 mmol) followed by 2-isocyanato-2-methyl-propane (7.2 μL, 0.063 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (16 mg, 64%). The product was isolated as a single enantiomer. LCMS for C24H30ClN8O2 (M+H)+: m/z=497.2; Found: 497.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C(O[C:26](=[O:31])C(Cl)(Cl)Cl)=O.[C:34]1([NH2:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:26]([NH:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccccc1
Reactant: O=C(OC(=O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution (4-methyl-3-nitrophenyl)amine (152 mg) in CH2Cl2 (15 mL) were added iPr2NEt (1.29 g) and trichloroacetic anhydride (370 mg) successively at 0° C. under a nitrogen atmosphere, and the mixture was stirred at 0° C. for 3 hr. To the solution was added phenylamine (930 mg), and the resulted mixture was stirred at room temperature for 16 h. The volatile materials were evaporated in vacuo. The residue was diluted with EtOAc (10 mL) and the resulted mixture was successively washed with 1M HCl (5 mL×2), saturated aqueous NaHCO3 (5 mL×2) and brine, dried over MgSO4 and filtered. The filtrate was evaporated in vacuo, and the residue was triturated with IPE. The precipitates produced were collected by filtration to give 1-(4-methyl-3-nitrophenyl)-3-phenylurea (270 mg).
Reaction SMILES: [F:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]2=[O:23])[CH2:3]1.[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH2:35])[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:35][CH:7]3[CH2:6][CH2:5][N:4]([CH2:9][CH2:10][N:11]4[C:20]5[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=5)[N:14]=[CH:13][C:12]4=[O:23])[CH2:3][CH:2]3[F:1])[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(=O)C(F)C3)c2c1
Reactant: NCc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)C(F)C3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.9 %

Procedure:
To 2 mL of a dichloromethane solution containing 48 mg of 1-(2-(3-fluoro-4-oxopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 30 mg of 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methaneamine, 26 μL of acetic acid was added, and stirred at room temperature for 1.5 hours. To the reaction mixture, 48 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography [eluent; chloroform:methanol=50:1], to give 31 mg of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-3-fluoropiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]3[N:12]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:13][CH2:14][C:10]=3[C:9]([C:20]([O:22]CC)=[O:21])=[N:8][C:7]=12)#[N:2].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]3[N:12]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:13][CH2:14][C:10]=3[C:9]([C:20]([OH:22])=[O:21])=[N:8][C:7]=12)#[N:2]
Reactant: CCOC(=O)c1nc2c(C#N)cnn2c2c1CCN2C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cnn2c3c(c(C(=O)O)nc12)CCN3C1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To 10.00 g (30.73 mmol) of ethyl 3-cyano-8-cyclopentyl-6,7-dihydro-8H-pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidine-5-carboxylate were added 200 ml of tetrahydrofuran and. 200 ml of ethanol. While stirring under cooling with ice water, 54 ml of a 1N aqueous solution of sodium hydroxide were added to the mixture, and stirring was continued for 1 hour at the same temperature. Furthermore, 500 ml of a 1:1 mixed solvent of tetrahydrofuran and ethanol were added, and the resultant mixture was stirred at the same temperature for a while. The reaction mixture was then acidified with concentrated hydrochloric acid, and insoluble solids were collected by filtration, washed with water and dried to give 9.09 g (yield: 91.04%) of the intended compound.
Reaction SMILES: COC1C(OC)=NS(=O)N=1.[CH3:11][N:12]([CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:21][CH2:22][CH2:23][NH2:24])[N:19]=1)[CH3:13].CN(CC1SC=C(CSC[CH2:37][NH:38][C:39]2[C:43](OC)=[N:42][S:41](=[O:46])[N:40]=2)N=1)C.CN>CO>[CH3:13][N:12]([CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:21][CH2:22][CH2:23][NH:24][C:43]2[C:39]([NH:38][CH3:37])=[N:40][S:41](=[O:46])[N:42]=2)[N:19]=1)[CH3:11]
Reactant: COC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Agent: CN
Agent: COC1=NS(=O)N=C1OC
Solvent: CO
Product: CNC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, Step A] is reacted with an equimolar amount of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared in Example 33, Step E] and the resulting 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide is treated with methylamine, the title compound is thereby produced.