Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[OH:25][C:26]1([CH2:50][CH2:51][CH2:52][OH:53])[CH2:31][C:30]2[CH:32]=[CH:33][C:34]([O:36][CH:37]([CH2:39][CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:38])=[CH:35][C:29]=2[O:28][C:27]1([CH3:49])[CH3:48].C(N(CC)CC)C.[C:61](OC(=O)C)(=[O:63])[CH3:62]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[C:61]([O:25][C:26]1([CH2:50][CH2:51][CH2:52][OH:53])[CH2:31][C:30]2[CH:32]=[CH:33][C:34]([O:36][CH:37]([CH2:39][CH2:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH3:38])=[CH:35][C:29]=2[O:28][C:27]1([CH3:48])[CH3:49])(=[O:63])[CH3:62]
Reactant: CC(CCCc1ccccc1)Oc1ccc2c(c1)OC(C)(C)C(O)(CCCO)C2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1(CCCO)Cc2ccc(OC(C)CCCc3ccccc3)cc2OC1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.4 %

Procedure:
To a solution of 3.177 g (7.96 mmole) dl-5-hydroxy-3-(3-hydroxypropyl)-2,2-dimethyl-7-(5-phenyl-2-pentyloxy)-3,4-dihydro-2H-benzopyran in 40 ml methylene chloride, under a nitrogen atmosphere, was added ;b 805 mg (7.96 mmole) triethylamine, the mixture stirred for 15 minutes and cooled to 0° C. At this temperature, 970 mg (7.79 mmole) 4-dimethylaminopyridine in 3 ml methylene chloride followed by 813 mg (7.96 mmole) acetic anhydride was added and the resulting mixture stirred at 0°-5° C. for one hour. After allowing the mixture to warm to room temperature, it was extracted three times with 30 ml portions methylene chloride. The extracts were washed with saturated sodium bicarbonate solution, dried (MgSo4) and evaporated to obtain 4.158 g of crude oil. The crude product was purified by column chromatography on silica gel eluting with ethyl ether/methylene chloride 3:97 (v/v) for 7 fractions and ;b 1:9 (v/v) for 43 fractions. Fractions 18-27 contained the diacetate. Fractions 28-45 containing desired monoacetate were combined and evaporated to afford 1.823 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]4[CH2:23][CH2:22]4)[C:13]3=[O:24])[N:8]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]2=[N:6][CH:7]=1.C([O-])(=O)C.[K+].C1(S)C=CC=CC=1>CO.[Pd]>[CH:21]1([N:14]2[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:12]([CH2:11][C:9]3[N:8]([CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[C:5]4=[N:6][CH:7]=[CH:2][CH:3]=[C:4]4[N:10]=3)[C:13]2=[O:24])[CH2:22][CH2:23]1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cc(Br)cnc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Sc1ccccc1
Solvent: CO
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2cccnc21
Temperature: 25 °C

Procedure:
To intermediate 16 (0.49 g, 1.09 mmol) in methanol (30 mL) were added potassium acetate (0.128 g, 1.3 mmol), thiophenol (0.5 mL) and wet 10% Pd/C (0.2 g). The reaction mixture was stirred at 25° C. under hydrogen atmosphere. After uptake of H2 (1 eq), the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in water and dichloromethane. The resulting mixture was successively extracted with dichloromethane dried over MgSO4 and concentrated. The residue was purified by column chromatography using dichloromethane/ methanol. The title compound 24 was collected as a white powder (333 mg, 81%). m/z=377 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCBr
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCOCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To a solution of (4-methoxyphenyl)methanol (76.3 g, 552.4 mmol) in anhydrous toluene (1 L) at 0° C. was added portionwise NaH (27.6 g, 630.5 mmol) over a period of 30 min, followed by ethyl 3-bromopropanoate (100 g, 552.4 mmol). The mixture was stirred at RT for 3 h and then quenched with 20% aqueous NH4Cl (500 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine, dried (Na2SO4) and then concentrated in vacuo to give ethyl 3-((4-methoxybenzyl)oxy)propanoate (112 g, 85%) as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH:3]1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.CN(CCN(C)C)C.[Li]CCCC.Cl[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30]>C1COCC1>[CH2:29]([O:28][P:27]([C:10]1[S:9][C:8]([CH:3]2[N:4]([CH3:7])[CH2:5][CH2:6][N:2]2[CH3:1])=[CH:12][CH:11]=1)(=[O:34])[O:31][CH2:32][CH3:33])[CH3:30]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CN1CCN(C)C1c1cccs1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(C2N(C)CCN2C)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 1,3-Dimethyl-2-thiophen-2-yl-imidazolidine (10 g, 60.17 mmol) in THF was added TMEDA (9.1 ml, 60.17 mmol), cooled to −78° C., then added 1.6 M nBuLi (47 ml, 75.21 mmol). After stirring at −78° C. for 30 min the mixture was warmed up to 0° C. in 1 hr and treated with diethyl chlorophosphonate (10.4 ml, 72.2 mmol). The reaction mixture was stirred at 0° C. for another 30 min. The reaction was then quenched by adding EtOAc and water. The EtOAc layer was separated and the water layer was further extracted with EOAc once. The combined EtOAc layers were dried over MgSO4, filtrated and concentrated to afford the crude product [5-(1,3-dimethyl-imidazolidin-2-yl)-thiophen-2-yl]-phosphonic acid diethyl ester (17 g). 1H NMR (300 MHz, DMSO-d6): δ 7.44 (m, 1H), 7.24 (m, 1H). 4.01 (m, 4H), 3.18 (m, 2H), 2.53 (m, 2H), 1.22 (m, 9H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:15][CH2:16][Cl:17])[P:5](Cl)([N:7]([CH2:11][CH2:12][Cl:13])[CH2:8][CH2:9][Cl:10])=[O:6].[CH2:18]([OH:21])[CH2:19][OH:20].CC(C)([O-])C.[K+].Cl>O.C(OC)(C)(C)C.O1CCCC1>[OH:20][CH2:19][CH2:18][O:21][P:5]([N:4]([CH2:3][CH2:2][Cl:1])[CH2:15][CH2:16][Cl:17])([N:7]([CH2:8][CH2:9][Cl:10])[CH2:11][CH2:12][Cl:13])=[O:6]
Reactant: OCCO
Reactant: O=P(Cl)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=P(OCCO)(N(CCCl)CCCl)N(CCCl)CCCl
Temperature: 0 °C

Procedure:
A 12-L, three-neck, round-bottom flask was equipped with an overhead mechanical stirrer, a thermometer and a nitrogen inlet/outlet bubbler. The flask was charged with N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidic chloride (979 g, 2.68 moles), 2, ethylene glycol (1.5 L, 26.8 moles), 4 and tetrahydrofuran (3 L). The stirrer was set to agitate at a moderate rate (to provide a clear red solution) and the mixture was cooled to 0° C. using an ice/water bath. To this cooled solution was added potassium tert-butoxide (362 g, 3.22 moles) over 20 minutes. The reaction mixture was then slowly warmed to room temperature and stirred for a total of 19 hours. A solution of hydrogen chloride in water (8 L, 1M) was introduced into the flask over 10 minutes. The organic fraction was collected and the aqueous fraction was extracted with ethyl acetate (2×4 L). The combined organic fractions were washed with saturated aqueous sodium chloride solution (1×4 L) and the solvents were removed under reduced pressure (30 mm Hg vacuum, final bath temperature at 50° C.) on a rotary evaporator to provide a dark reddish brown oil. This crude organic product was then dissolved with warm (40° C.) methyl tert-butyl ether (2 L) and allowed to cool to room temperature, stirring for a total of 14 hours. The resulting slurry was stirred for 30 minutes at 0° C. after which the precipitate was collected by vacuum filtration and washed with cold methyl tert-butyl ether (1 L). The combined filtrates were concentrated under reduced pressure (30 mmHg vacuum, final bath temperature at 50° C.) on a rotary evaporator to a volume of 500 mL and stirred for 30 minutes at 0° C. The resulting precipitate was collected by vacuum filtration and washed with cold methyl tert-butyl ether (200 mL). Two crops of solid product were then combined and dried overnight (30 mm Hg, 40° C.) to produce 2-hydroxyethyl-N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate, 3, as a tan powder (526 gm, 50% yield). TLC analysis showed one spot (Rf0.62; methanol:chloroform 1:9). Melting point: 76-78° C.; IR (KBr) 3372, 2957, 1459, 1344, 1206, 1098, 1053, 929 cm−1; MS (CI, methane) m/z 391(MH+), 353, 339, 248, 106. A thermal analysis (DSC) showed two exothermic decomposition ranges of 164-179 and 222-231 C.
Reaction SMILES: [OH:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1>CCOC(C)=O.[Pd]>[OH:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(C3=CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@@H](O)c2ncnc(C3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
5% Pd/C (10 mg) was added to a solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (17 mg, 0.05 mmol) in EtOAc (1 mL). The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The mixture was filtered through celite and concentrated to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidine-1-carboxylate as an oil (13 mg, 78%), which was used further without purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[N:14]=1.C1([O:23][C:24](=O)[NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.C1COCC1.C([O-])(O)=O.[Na+]>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:24]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]3[CH:6]=[CH:5][C:4]([CH:3]([O:2][CH3:1])[O:15][CH3:16])=[N:14][C:8]2=3)=[O:23])=[N:27][CH:28]=1)#[N:33]
Reactant: N#Cc1ccc(NC(=O)Oc2ccccc2)nc1
Reactant: COC(OC)c1ccc2c(n1)NCCCC2
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCCC2

Procedure:
A mixture of 2-(dimethoxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine (intermediate 237, 35 mg, 0.154 mmol), phenyl(5-cyanopyridin-2-yl)carbamate (intermediate 240, 122 mg, 0.509 mmol) and DMAP (28.3 mg, 0.231 mmol) in THF (1.7 ml) was heated at reflux for 23 h. The reaction mixture was diluted with sat. aq. NaHCO3 and extracted with DCM (3×). The combined organic layers were dried over Na2SO4 and evaporated. The crude material was applied to a 40 g RediSep® silica column and purified by normal phase chromatography, eluting with 99:1 DCM/MeOH. Product-containing fractions were combined and evaporated. The residue was triturated with Et2O and the solid removed by filtration. The filtrate was concentrated and the residue triturated with MeOH to give the title compound as a white solid. (UPLC-MS 6) tR 1.06; ESI-MS 368.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=3)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])[CH2:27][CH2:26]3)=[O:24])[C:8]=2[CH:37]=1)(O)=[O:2].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.N1C=CC=CC=1>[N:38]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]3[O:11][C:10]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=4)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]4[CH2:26][CH2:27][C@H:28]([N:31]5[CH2:35][CH2:34][CH2:33][C:32]5=[O:36])[CH2:29][CH2:30]4)=[O:24])[C:8]=3[CH:37]=2)=[O:2])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccc(C(=O)N3CCOCC3)cc2c1NC(=O)[C@H]1CC[C@H](N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-5-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (830 mg) obtained in Example 77 is suspended in N,N-dimethylformamide-pyridine (1:1, 30 ml), and thereto are added successively morpholine (196 mg), 1-hydroxybenzotriazole (406 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (576 mg) under ice-cooling, and the mixture is stirred at room temperature for 17 hours. To the reaction solution are poured ice-water and a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate, washed with water and a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform). The resulting residue is suspended in ethyl acetate-n-hexane, and the precipitates are collected by filtration, and dried to give the title compound (805 mg).
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]1[NH:35][N:34]=[C:33]([NH2:36])[CH:32]=1.NC1C=CNN=1>O1CCCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:36][C:33]3[CH:32]=[C:31]([C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)[NH:35][N:34]=3)[C:4](=[O:13])[NH:5]2)=[CH:10][CH:9]=1
Reactant: O=C1Nc2cc(F)ccc2/C1=C/O
Reactant: Nc1cc(-c2ccco2)[nH]n1
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: O=C1Nc2cc(F)ccc2C1=CNc1cc(-c2ccco2)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-furan-2-yl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one (0.033 gms.) is reacted with 0.061 gms. 5-furan-2-yl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (0.88 mL) to afford the named compound in the amount of 0.0263 gms.
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[N:25]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 24 h

Procedure:
A mixture of (2RS)-2-(2-cyano-l0-phenothiazinyl)-1-propyl methanesulphonate (10 g) and pyrrolidine (11.6 cc) in toluene (50 cc) is brought to 90° C. with stirring for 24 hours. After being cooled, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and the residue is taken up with ethyl ether (200 cc) and 4N aqueous sodium hydroxide solution (15 cc). After the mixture has been stirred for 10 minutes, settling is allowed to take place and the organic phase is washed with saturated aqueous sodium chloride solution (3×25 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 20° C. The residual oil (11.3 g) is dissolved in 0.5N aqueous hydrochloric acid solution (60 cc). This solution is washed with ethyl ether (100 cc) and then alkalinized with an excess of N aqueous sodium hydroxide solution and extracted with ethyl ether (100 cc). The organic phase is washed with saturated aqueous sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 20° C. The residual yellow oil (9.5 g) is purified on a column (height: 30 cm; diameter: 5.8 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (95:5 by volume) (1 liter) of methylene chloride and methanol and collecting 100-cc fractions. Fractions 3 to 10 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[(2RS)-l-(l-Pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonitrile (5.45 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:10]([C:11](N(OC)C)=[O:12])=[CH:9][C:8]([Br:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1)[CH3:19]>C1COCC1>[Br:1][C:2]1[C:10]([C:11]([C:23]2[CH:24]=[CH:25][C:20]([CH2:18][CH3:19])=[CH:21][CH:22]=2)=[O:12])=[CH:9][C:8]([Br:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2
Reactant: CCc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cc(Br)c2c(c1Br)CCC2
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cc(Br)c3c(c2Br)CCC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.9 %

Procedure:
To a solution of amide 9 (0.27 g, 0.73 mmol) in anhydrous THF (2.7 mL) was added dropwise 4-ethylphenylmagnesium bromide (3.65 mL of 0.5M in THF, 1.83 mol) at 0° C. under nitrogen atmosphere. The mixture was warmed up to room temperature slowly and stirred at room temperature for 15 h. The reaction mixture was quenched with 1M HCl solution (10 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 10 (0.25 g, 0.62 mmol, 85%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:13][CH2:14][C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[N:4]=1)#[N:2].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:8]1[N:7]=[C:6]2[N:5]([CH2:13][CH2:14][C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[N:4]=[C:3]([C:1]#[N:2])[C:11]2=[CH:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2c1ccc[n+]2[O-]
Product: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2nc(Cl)ccc12
Temperature: 75 °C
Reaction time: 9 h

Procedure:
To the intermediate from Step A above (225 mg, 0.735 mmol) was added POCl3 (2.8 g, 18.3 mmol) and the mixture was stirred at 75° C. for 9 hours. The reaction mixture was then concentrated in vacuo to remove POCl3. To the residue was added hexane/ethyl acetate (2/1, 50 mL) and the pH adjusted to 7.5˜8.0 with aqueous K2CO3 at 0° C. The water layer was extracted with the hexane/ethyl acetate (2/1, 2×20 mL). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using hexane/ethyl acetate eluent to give the product as a white solid. 1H NMR (500 MHz, CDCl3): δ 2.86 (m, 2H); 4.90 (t, J=8.4 Hz, 2H); 7.42 (d, J=8.4 Hz, 1H); 8.17 (d, J=8.4 Hz, 1H), m/z=325.04 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:13]=[C:12]2[N:4]([C:5](=[O:19])[N:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]3[N:8]=[CH:9][NH:10][C:11]=32)[N:3]=1.[Br:20]N1C(=O)CCC1=O.C1(O)C=CC=CC=1>C1COCC1>[Br:20][C:9]1[NH:10][C:11]2[C:12]3=[N:13][C:2]([CH3:1])=[N:3][N:4]3[C:5](=[O:19])[N:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]=2[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c(=O)n2nc(C)nc2c2[nH]cnc21
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCCCCn1c(=O)n2nc(C)nc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of 8-methyl-4-pentyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (20 mg, 0.078 mmol) in THF (5 mL) was added N-Bromosuccinimide (19 mg, 0.11 mmol). After stirring at room temperature for 1 hour, phenol was added to quench the reaction. The reaction mixture was concentrated at reduced pressure, and the residue was purified by preparative LCMS (method B) to yield the desired product as white powder. LCMS calculated for C12H16BrN6O (M+H): 339.1. found: 339.0, 341.0.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Cc1ccc(NC(=S)Nc2ncccc2OCc2c(F)cccc2Cl)cc1
Product: Cc1ccc(NC(=N)Nc2ncccc2OCc2c(F)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of yellow mercuric oxide (0.65g, 0.0025 mol), N-[3-(2-chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-4-methylphenylthiourea (1 .0g, 0.0025 mol) and methanolic ammonia solution (30 ml) was stirred for 3 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by recrystallisation from ethanol gave the desired product. Yield 0.55 g, (57%), m.p. 136°-138 ° C.
Reaction SMILES: Cl[C:2]([N:14]=[C:15]=[O:16])([C:10](F)([F:12])[F:11])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[Cl:5]>CCOCC.[Zn]>[F:11][C:10]([F:12])=[C:2]([N:14]=[C:15]=[O:16])[C:3]([F:8])([F:9])[C:4]([F:6])([F:7])[Cl:5]
Reactant: O=C=NC(Cl)(C(F)(F)F)C(F)(F)C(F)(F)Cl
Agent: [Zn]
Solvent: CCOCC
Product: O=C=NC(=C(F)F)C(F)(F)C(F)(F)Cl

Procedure:
By the procedure of Example 2, adding 1,3-dichloro-1-(trifluoromethyl)tetrafluoropropyl isocyanate to a suspension of powdered zinc in ether will yield 2,2-difluoro-1-(2-chlorotetrafluoroethyl)vinyl isocyanate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19][CH2:20][CH:21]=[CH:22][CH2:23]Br.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:23][CH:22]=[CH:21][CH2:20][Br:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC=CCBr
Reactant: O=C(NCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N(CC=CCBr)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of N-benzyloxycarbonylbenzylamine (50 g), 1,4-dibromo-2-butene (44 g) and NaH (10.7 g, 60% in oil) in 350 ml of DMF is stirred at 0° C. for 1 h and then at 25° C. for 3 h. The reaction mixture is subjected to aqueous workup and the residue obtained is purified by chromatography over SiO2. The title compound is obtained as an oil having characterization data as indicated below.
Reaction SMILES: [CH:1]1[C:17]2[C:9]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.B(O)O>>[C:1]1([C:7]2[C:8]3[O:12][C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:9]=3[C:17]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]=2)[CH:17]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)ccc1oc3ccccc3c12
Agent: OBO
Product: c1ccc(-c2cc3ccccc3c3c2oc2ccccc23)cc1

Procedure:
In this reference example, a position was specified where the benzo[b]naphtho[1,2-d]furan which was synthesized as an intermediate in each of Synthesis Example 1 and Synthesis Example 2 was converted into boronic acid in the reaction scheme (E1-3). Specifically, 6-phenylbenzo[b]naphtho[1,2-d]furan (abbreviation: PBnf) was synthesized using the compound synthesized in the reaction scheme (E1-3), and was subjected to X-ray crystallography.