Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.I[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13]([CH:21]([CH3:23])[CH3:22])[N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:21]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[N:12]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cncnc2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of 5-Pyrimidinylboronic acid (15 mg, 0.14 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 ml). Pd(PPh3)4 (15 mg, 0.015 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O) to yield BA53. ESI-MS (M+H)+ m/z calcd 256.1, found 256.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:22]5[CH:27]=[CH:26][C:25]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)=[CH:24][CH:23]=5)[CH:19]=4)[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)[C:6]([O:35][CH3:36])=[CH:5][C:4]=1[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38].[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:22]5[CH:23]=[CH:24][C:25]([N:28]6[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]6)=[CH:26][CH:27]=5)[CH:19]=4)[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)[C:6]([O:35][CH3:36])=[CH:5][C:4]=1[CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]
Reactant: COc1cc(-c2ccnc3[nH]c4ccc(-c5ccc(N6CCN(C)CC6)cc5)cc4c23)c(OC)cc1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(O)c2ccccc2)c(OC)cc1-c1ccnc2[nH]c3ccc(-c4ccc(N5CCN(C)CC5)cc4)cc3c12
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of (2,5-dimethoxy-4-(6-(4-(4-methylpiperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indol-4-yl)phenyl)(phenyl)methanone (example 50, 39.8 mg, 0.0683 mmol) in CH2Cl2/MeOH 5:2 (2 mL), NaBH4 (6 mg, 2.3 eq) was added. After stirring for 1 h20 at r.t., the reaction mixture was quenched with sat. aq. NH4Cl (5 mL), diluted with CH2Cl2 (25 mL) and washed with water (30 mL) The organic layer was collected and the aqueous layer washed four times with CH2Cl2 (20 mL) The combined organic layers were washed with brine and dried over MgSO4, filtered and evaporated to dryness. A white solid was obtained in 66% yield (26.3 mg) after trituration of the crude product in DCM and filtration. 1H NMR (300 MHz, DMSO, 80° C.) δ 11.61 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 7.63 (dd, J=8.4, 1.9 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.49-7.41 (m, 4H), 7.35-7.15 (m, 5H), 7.08 (d, J=5.0 Hz, 1H), 7.02 (s, 1H), 6.98-6.79 (m, 2H), 6.11 (d, J=4.9 Hz, 1H), 5.67 (d, J=5.4 Hz, 1H), 3.69 (s, 3H), 3.62 (s, 3H), 3.24-3.14 (m, 4H), 2.54-2.47 (m, 4H), 2.27 (s, 3H); 13C NMR (75 MHz, DMSO, 80° C.) δ 152.2 (C), 150.2 (C), 149.6 (C), 149.2 (C), 145.2 (CH), 144.8 (C), 140.6 (C), 137.6 (C), 135.1 (C), 131.0 (C), 131.0 (C), 127.5 (CH), 126.3 (CH), 126.2 (CH), 126.1 (CH), 125.9 (C), 124.3 (CH), 121.8 (C), 120.7 (C), 118.6 (CH), 116.1 (CH), 115.3 (CH), 113.4 (CH), 111.0 (CH), 110.6 (CH), 68.1 (CH), 55.9 (OCH3), 55.8 (OCH3), 54.3 (2CH2), 47.8 (2CH2), 45.3 (NCH3); MS (ESI) m/z: 585.5 [M+H]+; 1170.1 [2M+H]+; 567.3 [M-OH]+; HRMS calcd for C37H37N4O3 [M+H]+ 585.2860 found 585.2868.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[C:11]([CH2:13][C:14](OC)=[O:15])#[N:12].C[O-].[Na+]>CO>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[CH:4]=[C:13]([C:11]#[N:12])[C:14](=[O:15])[NH:1]2
Reactant: COC(=O)CC#N
Reactant: Nc1cccc(F)c1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc2c(F)cccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
To a solution of MeOH (60 mL) containing 2-amino-6-fluoro-benzaldehyde (1.19 g, 8.6 mmol) and methyl cyanoacetate (0.91 mL, 10.3 mmol) was added sodium methoxide (2.93 mL, 12.8 mmol, 25% in MeOH). The mixture was stirred at rt for 16 hrs. The resulting yellow precipitates were filtered, washed with MeOH and then stirred in 1N HCl (75 mL) for 2 hrs at rt. The solid was filtered, washed with water and dried in vacuo to yield 5-fluoro-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (1.2 g) as a white solid. MS [M+H]+: 189.1; tR=2.00 min. (method 1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[CH2:32]([NH:39][C:40](=[O:43])[CH2:41]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:41][C:40]([NH:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:43])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Reactant: O=C(CCl)NCc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(OCC(=O)NCc2ccccc2)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared by alkylation of N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester with N-benzyl-2-chloroacetamide (potasium carbonate, sodium iodide, refluxing butanone under Argon overnight). The product was purified by flash column chromatography (silica, 1:1 hexane:EtOAc) to afford the methyl ester as a white solid, mp 57-59° C.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[C:12]([Br:24])[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=1)[CH3:6].[OH:32][CH2:33][C:34]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1>ClCCl.C1CCCCC1>[Br:24][C:12]1[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=[C:15]2[C:11]=1[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=[C:7]2[CH:5]([O:32][CH2:33][C:34]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])[CH2:36][CH2:35]1)[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2c(Br)n(COCC[Si](C)(C)C)nc12
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2c(Br)n(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(3-Bromo-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (1.29 g, 2.21 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.71 g, 2.43 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 8 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (60 μL, 0.44 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate and diluted with diethyl ether and the layers separated. The ethereal was washed with water (2×), 1 M potassium bisulfate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10% ethyl acetate/hexanes) gave 840 mg (53%) as a yellow film. 1H-NMR (CDCl3, 500 MHz) δ 7.82 (s, 1H), 7.54 (s, 1H), 7.24-7.27 (m, 2H), 7.18-7.22 (m, 3H), 5.51 (s, 2H), 5.07 (q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.44-3.51 (m, 2H), 3.27 (d, J=9.2 Hz, 1H), 3.24 (d, J=9.2 Hz, 1H), 2.99-3.03 (m, 2H), 2.11-2.16 (m, 2H), 1.82-1.88 (m, 2H), 1.50 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 0.70-0.83 (m, 2H), 0.08 (s, 9H). Mass spec.: 736.03 (MNa)+.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH3:24][O:25][CH2:26][CH2:27][OH:28]>>[CH3:24][O:25][CH2:26][CH2:27][O:28][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1
Reactant: COCCO
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Potassium tert.-butoxide (46.5 g, 475 mmol) was added to 2-methoxyethanol (200 mL) in 20 min at room temperature, then 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (30 g) was added and the resulted mixture was heated at 80-90° C. for about 3 h. Evaporation of most of the solvent, to the residue was added 100 ml of water, stirred for 1 h at 0° C., filtered and dried. This gave product (30 g, 87%) that was almost identical to that from Intermediate 119, method A.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=O)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>CO>[NH2:1][C:2]1[C:7]([C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1nccnc1N
Reactant: C1CCNC1
Solvent: CO
Product: Nc1nccnc1C(=O)N1CCCC1

Procedure:
A solution of 10 g. (0.065 mol) of methyl 2-aminopyrazine-3-carboxylate in 100 ml. of methanol and 25 ml. of pyrrolidine was refluxed for 18 hours. The residue obtained after evaporation under reduced pressure was triturated with ether to yield 8.8 g. (70%) of the above-named product as yellow crystals, with m.p. 100°-105°. A second crop of 2.3 g. (18%) with m.p. 95°-105° was obtained from the mother liquors. The analytical sample was recrystallized from 2-propanol. The pale yellow prisms had a melting point of 104°-106°.
Reaction SMILES: [Cl-].[NH4+].[O:3]=[C:4]([N:24]1[CH2:29][CH2:28][N:27]([C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])[CH2:26][CH2:25]1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)=[CH:11][CH:10]=1)=[O:8]>C1COCC1.O.[Fe]>[O:3]=[C:4]([N:24]1[CH2:25][CH2:26][N:27]([C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:39])([F:40])[F:38])[CH2:28][CH2:29]1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(-c2ccc(C(=O)NCC(=O)N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)cc2)c1
Yield: 49.3 %

Procedure:
Ammonium chloride (74 mg, 1.4 mmol) was added to a stirred solution of 3′-nitro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (prepared by the method as described above) (123 mg, 0.2 mmol) in a mixture of THF (6 mL) and H2O (4 ml). Iron powder (77 mg) was then added and the resulting mixture at reflux temperature for 3 hrs. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in EtOAc, washed with 5% aqueous NaHCO3 solution, followed by saturated brine solution. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 69 mg (49.3% yield) of 3′-Amino-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 92.88%. 1H NMR (CDCl3): δ 7.9 (d, 2H), 7.8-7.7 (bd, 1H), 7.7-7.6 (m, 4H), 7.6-7.55 (bs, 1H), 7.4-7.3 (d, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 6.9 (t, 1H), 6.8 (d, 1H), 4.38-4.3 (m, 1H), 4.3-4.22 (m, 1H), 4.08-3.96 (bd, 2H), 3.94-3.86 (bs, 1H), 3.84-3.64 (m, 4H), 3.64-3.32 (m, 2H), 3.52-3.46 (d, 1H), 3.44-3.4 (t, 1H), 3.3-3.2 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:22])=[C:4]([CH:7]=[C:8]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([F:21])(=[O:20])=[O:19])[CH:13]=2)[CH:9]=1)[CH:5]=O.Cl.[NH2:24][OH:25].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[C:3]([OH:22])=[C:4]([CH:7]=[C:8]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([F:21])(=[O:20])=[O:19])[CH:13]=2)[CH:9]=1)[CH:5]=[N:24][OH:25]
Reactant: NO
Reactant: O=Cc1cc(N=Nc2cccc(S(=O)(=O)F)c2)cc(Cl)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)(F)c1cccc(N=Nc2cc(Cl)c(O)c(C=NO)c2)c1
Temperature: 25 °C

Procedure:
3-Chloro-5-(3-fluorosulfonylphenylazo)-2-hydroxy-benzaldehyde (23.8 g, 0.07 mol) was added to 250 ml ethanol, followed by hyroxylamine hydrochloride (5.04 g, 0.072 mol) and sodium hydroxide (2.88 g, 0.072 mol). The reaction was brought to reflux for 30 minutes and then cooled to room temperature. The mixture was then poured into ice and hydrochloric acid, resulting in the formation of a precipitate which was filtered off, washed with water, and dried in a vacuum oven (55° C.). The yield was 22.5 g (90%).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8]([F:19])([F:18])[C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:22]([C@:24]1([OH:31])[CH2:28][CH2:27][N:26]([CH3:29])[C:25]1=[O:30])#[CH:23]>>[F:18][C:8]1([F:19])[C:9]2[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[N:11][C:10]=2[C:4]2[CH:3]=[C:2]([C:23]#[C:22][C@:24]3([OH:31])[CH2:28][CH2:27][N:26]([CH3:29])[C:25]3=[O:30])[CH:21]=[CH:20][C:5]=2[O:6][CH2:7]1
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: COC(=O)c1nc2c(s1)C(F)(F)COc1ccc(Br)cc1-2
Product: COC(=O)c1nc2c(s1)C(F)(F)COc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Methyl 9-bromo-4,4-difluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford crude (R)-methyl 4,4-difluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate. Crude (R)-methyl 4,4-difluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was subjected to General Procedure M to afford 21.2 mg (38%) of 4,4-difluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxamide. M+1=420; 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.63 (d, J=2.2 Hz, 1H), 8.15 (s, 1H), 7.49 (dd, J=8.4, 2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.43 (s, 1H), 4.76 (t, J=10.6 Hz, 2H), 3.43-3.29 (m, 2H), 2.81 (s, 2H), 2.46 (ddd, J=12.8, 6.4, 5.1 Hz, 1H), 2.26-2.15 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:19][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:2]([F:1])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: N#Cc1ccccc1-c1ccc(CO)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1ccc(CBr)cc1F
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution (150 mL) of 2′-fluoro-4′-(hydroxymethyl)biphenyl-2-carbonitrile (14.1 g) in toluene was added phosphorus tribromide (18.7 g) at room temperature, and the mixture was stirred for 16 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and the obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (15.3 g, 100%).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][SH:12].P([O-])([O-])([O-])=O>CO>[C:2]1([C:1]2[S:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: N[C@@H](CS)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Product: O=C(O)C1CSC(c2ccccc2)=N1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
Benzonitrile (40 mmol) was combined with L-cysteine (45 mmol) in 100 mL of 1:1 MeOH/pH 6.4 phosphate buffer solution. The reaction was stirred at 40° C. for 3 days. The precipitate was removed by filtration, and MeOH was removed using rotary evaporation. To the remaining solution was added 1M HCl to adjust to pH=2 under 0° C. The resulting precipitate was filtered to yield a white solid 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid 42a, which was used directly to next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29]([CH:31]1[O:33][CH2:32]1)Cl.C(#N)C>O>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:7]2[C:6](=[O:22])[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:29][CH:31]4[CH2:32][O:33]4)=[CH:3][CH:4]=3)[O:9][CH:8]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1OC
Reaction time: 4 h
Yield: 70.6 %

Procedure:
A mixture of 7-hydroxy-3′,4′-dimethoxyisoflavone (2, 0.30 g, 1 mmol), K2CO3 (0.41 g, 3 mmol), epichlorohydrin (0.3 g, 3 mmol) and acetonitrile (30 mL) was refluxed with stirring for 4 hrs (TLC monitoring). The mixture was evaporated in vacuo to give a residue which was treated with H2O (50 mL). The precipitate thus formed was collected, purified by column chromatography (MeOH/CH2Cl2=1:100), and crystallized from EtOH to give the title compound 4 (0.25 g, 70% yield). M.p.: 161-162° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=1.CO>[Pd].CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)CCc1cccnc1
Yield: 100.6 %

Procedure:
A mixture of 5.0 g of 3-(3-pyridyl)acrylic acid, 0.4 g of 10% palladium on activated carbon, 150 ml of methanol, and 50 ml of dimethylformamide is hydrogenated at room temperature and atmospheric pressure. After removal of the catalyst by filtration, the filtrate is concentrated to give 5.1 g of the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]1([SH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>CS(C)=O>[CH:7]1([S:13][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=Cc1ccccc1F
Reactant: SC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccccc1SC1CCCCC1
Temperature: 100 °C
Yield: 90.1 %

Procedure:
To a stirred suspension of K2CO3 (4.5 g, 32.6 mmol) and cyclohexylmercaptan (2.0 mL, 16.4 mmol) in DMSO (20 mL) was added 2-fluorobenzaldehyde (1.7 mL, 16.2 mmol) dropwise over 10 minutes at room temperature, and the reaction mixture was heated at 100° C. for 5 hours with stirring. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous phase extracted with ethyl acetate (×3). The combined organic extracts were washed successively with sodium bicarbonate solution and brine, then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 2-(cyclohexylthio)benzaldehyde (3.22 g, 14.6 mmol, 90%) which was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][C:8]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:7]2
Reactant: O=C1CCc2cccc(Br)c2C1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: Brc1cccc2c1CCC(N1CCCC1)=C2

Procedure:
To a solution of 8-bromo-2-tetralone (10 gm, 44.4 mMol) in toluene (175 ml) was added pyrrolidine (6.6 ml), and the solution was stirred at reflux for three hours. The volatiles were removed in vacuo to give 8-bromo-3-pyrrolidino-1,2-dihydronaphthalene as a brown oil. To this oil in p-dioxane (60 mL) was added methyl iodide (20 mL, 322 mMol), and the resulting solution was stirred at reflux for eighteen hours. The reaction mixture was diluted with water (60 mL) and acetic acid (3.2 mL), and heating was continued for an additional three hours. After this time the solution was cooled to room temperature and the volatiles removed in vacuo. The residue was suspended in water and extracted well with diethyl ether. The organic phases were combined, washed with saturated aqueous NaHCO3, dried with Na2SO4 and concentrated in vacuo to give an orange oil. Purification by flash chromatography (33% diethyl ether in hexane) gave the title compound as a light orange oil (6.88 gm, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].F[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[C:9]([O:8][C:7]([NH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:16]=[CH:15][CH:14]=1)[O:1][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2cccc(CNC(=O)OC(C)(C)C)c2)cc1
Temperature: 100 °C
Yield: 101.7 %

Procedure:
tert-Butyl (3-hydroxybenzyl)carbamate (0.025 g, 0.11 mmol) was dissolved in acetonitrile (1.0 mL) with methyl 4-fluorobenzoate (Aldrich, Cat 120707) (0.034 g, 0.22 mmol) and cesium carbonate (0.073 g, 0.22 mmol) in a sealed tube. The reaction was heated to 100° C. for 2 h. and was complete. The reaction was taken up in ethyl acetate, filtered and concentrated under reduced pressure to give crude methyl 4-(3-((tert-butoxycarbonylamino)methyl)phenoxy)benzoate (0.040 g) as a clear oil.
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[CH:3]=[CH:2]1.[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C=CCCCC
Reactant: O=C1C=CC(=O)O1
Product: C=CCCCCCCCC

Procedure:
The same procedure as in Example 1 was performed with the exception that 100 parts of (A-2), 116.8 parts of maleic anhydride and 50.5 parts of 1-hexene (C-2) (SP value: 7.5) were used in place of 100 parts of (A-1), 24 parts of maleic: anhydride and 18.5 parts of 1-decene (C-1) in Example 1, to obtain a modifier for polyolefin resin. (K-5) containing a copolymer (X-5). The (X-5) had an SP value of 9.9, an acid value of 250 and an Mn of 2,500.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:8])[O:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:2][C:3]2[O:4][C:5](=[O:8])[O:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=c1occ(CBr)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1occ(CSc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
In 30 ml of dichloromethane was dissolved 1.0 g of 4-bromomethyl-1,3-dioxol-2-one, and 0.8 g of 4-fluorobenzenethiol was added. Then, 0.6 g of triethylamine was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1 [except that the column was eluted with a mixture of chloroform and n-hexane (2/1, v/v)]. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 0.52 g of the captioned compound as pale yellow crystals.