Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([OH:19])=[O:18].CC(O)=O>CCOC(C)=O>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc(C(=O)O)cc3)nc12

Procedure:
4-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzoic acid was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 4-carboxyphenylboronic acid following general procedures as described in these Examples. Silica gel chromatography using 50-100% [5% AcOH:EtOAc]/Hexanes as eluant gave 10 mg (6%) of a pale brown solid. M+H=324.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([C:39]3([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)O1>>[CH2:1]([S:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:33]2[CH:34]=[CH:35][C:36]([C:39]3([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])[CH2:41][CH2:40]3)=[CH:37][CH:38]=2)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CSCc1ccccc1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1[C@H](O)CSCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 2, using (S)-2-benzylsulfanyl-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: [C:1]1([CH3:49])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[C:22](C4C=CC(C)=CC=4)=[C:21]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]([NH:36][CH2:37][C:38]([O:40]C)=[O:39])=[O:35])[N:20](C4C=CC(C)=CC=4)[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([CH3:49])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:22]=[C:21]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]([NH:36][CH2:37][C:38]([OH:40])=[O:39])=[O:35])[NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)CNC(=O)CCCCc1c(-c2ccc(C)cc2)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2n1-c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3cc(CCCCC(=O)NCC(=O)O)[nH]c3nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 2-(5-(2,3-di-p-tolyldi-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanamido)acetate (step 1) (17 mg, 0.036 mmol) in THF (1 ml) and water (0.5 ml) was treated with LiOH. monohydrate (8.12 mg, 0.108 mmol). After stirring at room temperature for 3 hours, the reaction mixture was treated with water (20 ml) and the pH adjusted to pH 2 using 2M HCl. The aqueous portion was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure. Purification by reverse phase (C18) chromatograpy eluting with 0-30% MeCN in water (0.1% TFA) afforded the titled compound;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]2[CH2:21][C@H:22]([O:24][C:25]3[CH:30]=[N:29][C:28]([CH:31]4[CH2:33][CH2:32]4)=[CH:27][N:26]=3)[CH2:23][C@H:17]2[CH2:16]1)(=[O:14])=[O:13].[Cu][C:35]#[N:36]>CN(C)C=O>[CH:31]1([C:28]2[N:29]=[CH:30][C:25]([O:24][C@H:22]3[CH2:21][N:18]4[CH2:19][CH2:20][N:15]([S:12]([C:3]5[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=5[C:35]#[N:36])(=[O:14])=[O:13])[CH2:16][C@@H:17]4[CH2:23]3)=[N:26][CH:27]=2)[CH2:33][CH2:32]1
Reactant: N#C[Cu]
Reactant: O=S(=O)(c1cc(C(F)(F)F)ccc1Br)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)cc1S(=O)(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a solution of Example 201A (105 mg, 0.192 mmol) in N,N-dimethylformamide (1 mL) was added copper(I) cyanide (52 mg, 0.58 mmol), and the resulting mixture was heated at 120° C. and stirred for 24 hours. The cooled mixture was partitioned between water and ethyl acetate, and the organic layer was dried over Na2SO4. The drying agent was removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified on silica gel using a solvent gradient of 0-60% ethyl acetate in hexanes. The title compound was obtained as a colorless solid (70 mg, 74%). 1H NMR (300 MHz, CDCl3) δ ppm 0.88-0.99 (m, 4H), 1.77-1.91 (m, 1H), 1.93-2.06 (m, 2H), 2.35 (dd, J=10.00, 5.26 Hz, 1H), 2.39-2.61 (m, 3H), 2.81-2.96 (m, 1H), 3.03 (dd, J=8.82, 2.37 Hz, 1H), 3.68 (dd, J=10.17, 6.78 Hz, 1H), 3.89 (dd, J=10.51, 1.70 Hz, 1H), 3.96-4.08 (m, 1H), 5.23-5.39 (m, 1H), 7.90-7.98 (m, 2H), 7.99-8.06 (m, 2H), 8.30 (s, 1H); MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10](I)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C@@:20]12[O:28][CH2:27][O:26][N:22]([CH2:23][C@H:24]1[CH3:25])[C:21]2=[O:29].C(=O)([O-])[O-].[K+].[K+].N>CN1CCCC1=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:22]2[CH2:23][C@:24]3([O:26][CH2:27][O:28][C@@:20]3([CH3:19])[C:21]2=[O:29])[CH3:25])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN2OCO[C@@]1(C)C2=O
Reactant: COCOc1ccc(I)nc1Cc1ccccc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COCOc1ccc(N2C[C@@]3(C)OCO[C@@]3(C)C2=O)nc1Cc1ccccc1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 54.5 %

Procedure:
3.6 g of 2-benzyl-3-methoxymethyloxy-6-iodopyridine (Production Example 12), 1.5 g of (3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinone synthesized by a method known in literature (J. Org. Chem., 1969, 34, 675), 1.1 g of cuprous iodide and 3.3 g of potassium carbonate were suspended in 20 ml of 1-methyl-2-pyrrolidinone, followed by heating stirring at 140° C. for 20 minutes in an oil bath in a nitrogen atmosphere. After cooling as it was, ethyl acetate and aqueous ammonia were added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate anhydride and the solvent was removed. The residue was subjected to silica gel column chromatography using 20-50% ethyl acetate/hexane as an eluent for separation and purification, to give 2 g of the target compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:29][NH2:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[C:17]([CH3:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)ccc1OCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)(F)F
Yield: 99 %

Procedure:
The title compound is prepared in 99% yield (460 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.26 mmol) and (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (353 mg, 1.38 mmol, Amine-34) in a similar manner to Intermediate-2.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[C:15]([OH:16])=[CH:14][C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=1.[CH3:21][N:22]1CCCC1=O>>[C:21]([C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[C:15]([OH:16])=[CH:14][C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=1)#[N:22]
Reactant: CN1CCCC1=O
Reactant: Oc1cc2c(cc1CC=Cc1ccccc1Br)OCC2
Product: N#Cc1ccccc1C=CCc1cc2c(cc1O)CCO2
Temperature: 25 °C

Procedure:
6-(o-Bromocinnamyl)-2,3-dihydro-5-hydroxy-benzofuran (1.49 g; 4.5 mM) and cuprous cyanide (1.37 g; 15.3 mM) were suspended in 18 ml of anhydrous N-methyl-2-pyrollidinone. Nitrogen was bubbled through this suspension for approximately 15 minutes and the reaction mixture was then heated to 175° under nitrogen for 2 hours. After cooling to ambient temperature the reaction was poured into 60 ml of water containing 60 ml of concentrated ammonium hydroxide. This emulsion was extracted three times with ether, dried over magnesium sulfate and stripped to a brown oil. Flash chromatography of this material on a 30 mm by 51/2" column of silica gel eluted with 500 ml of 35% ethyl acetate in hexane gave a solid which was recrystallized from ethyl acetate/hexane producing 0.95 g (76%) of white crystals identified as 6-(o-cyanocinnamyl)-2,3-dihydro-5-hydroxy-benzofuran.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[N:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[C:26]([CH2:29][CH2:30][C:31](O)=[O:32])[S:27][CH:28]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:25]=[C:26]([CH2:29][CH2:30][C:31]([NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:8]([C:5]4[N:4]=[C:3]([C:2]([F:15])([F:1])[F:16])[O:7][N:6]=4)[CH:9]=3)=[O:32])[S:27][CH:28]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)CCc1nc(-c2ccc(F)cc2)cs1
Reactant: Nc1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(CCc1nc(-c2ccc(F)cc2)cs1)Nc1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 43 %

Procedure:
This compound was synthesized from 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline and 3-(4-(4-fluorophenyl)thiazol-2-yl)propanoic acid as described in example 8 step 6 (80 mg, yield 43%). 1H NMR (400 MHz, CDCl3) δ 8.80 (br s, 1H), 8.11 (s, 1H), 7.88-7.83 (m, 4H), 7.48-7.44 (t, J=7.9 Hz, 1H), 7.33 (s, 1H), 7.14-7.10 (t, J=8.7 Hz, 2H), 3.52-3.48 (m, 2H), 3.04-3.01 (m, 2H). MS (ESI) m/z: Calculated for C21H14F4N4O2S: 462.08. found: 463.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]=[S:13])[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]([NH:15][NH2:16])=[S:13])[CH3:2]
Reactant: NN
Reactant: CCc1cc(OC)ccc1N=C=S
Solvent: CCO
Solvent: O
Product: CCc1cc(OC)ccc1NC(=S)NN
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of 2-ethyl-1-isothiocyanato-4-methoxybenzene (4.9 g, 25 mmol) in ethanol (22 mL), was added slowly, hydrazine hydrate (1.3 g, 28 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and diluted with ethyl acetate (250 mL) and washed with water (2×50 mL), followed by brine (2×50 mL). The organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure. Purification by flash column chromatography using 0-40% ethyl acetate/hexanes as eluent provided the title compound as a white solid (4.9 g, 86%): mp 113-115° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.89 (s, 1H), 7.20-7.19 (m, 1H), 6.77-6.71 (m, 2H), 4.71 (bs, 2H), 3.74 (s, 3H), 2.52-2.47 (m, 2H), 1.13-1.08 (m, 3H); ESIMS m/z 224 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:19]/[C:20](=[O:21])[CH3:22]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)/C=C/c1ccccc1Cl
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
In a 250 ml single neck flask was charged 14 g (99.6 mmoles, 1.0 eq) of o-chlorobenzaldehyde dissolved in 30 ml of acetone. To this was added 5 g of a 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 13.8 g of (E)-4-(2-chlorophenyl)-3-buten-2-one as a faintly yellow oil in 76.9% yield.
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:5](=[CH2:6])[C:2]2([CH3:4])[CH3:3].[CH:11](=[O:13])[CH3:12].CC1C=CC(C)=CC=1C>>[CH3:3][C:2]1([CH3:4])[CH:1]2[CH2:10][CH:7]([CH2:8][CH2:9]2)[CH:5]1[CH2:6][C:11](=[O:13])[CH3:12]
Reactant: CC=O
Reactant: C=C1C2CCC(C2)C1(C)C
Agent: Cc1ccc(C)c(C)c1
Product: CC(=O)CC1C2CCC(C2)C1(C)C
Yield: 40.5 %

Procedure:
A 1 liter water jacketed photochemical reaction vessel equipped with magnetic stirrer and pyrex immersion well is charged with 418 g camphene (807, Aldrich) and 372 g acetaldehyde and 30 g diacetyl (photochemical hydrogen abstractor). The mixture is irradiated with a 450 medium pressure mercury lamp (Hanovia) for 55 hours, during which time five 30 g portions of diacetyl are added at varying intervals. The reaction mixture is combined with 150 g of 1,2,4-trimethyl benzene and washed with water. The material is distilled without fractionation and then redistilled through a 5 foot Vigreux column to yield 224 g colorless product, b.p. 70°-72° (55 mm Hg).
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[O:6][C:5]=1[NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])(=O)[CH3:2].[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:19]1([C@@H:16]([NH:15][C:5]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:1]=2[CH3:2])=[O:6])[CH2:17][CH3:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NNc1ccccc1
Reactant: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(C)n(Nc2ccccc2)c(=O)c2ccccc12)c1ccccc1
Temperature: 160 °C
Yield: 66.4 %

Procedure:
A mixture of 4-acetyl-3-((S)-1-phenyl-propylamino)-isochromen-1-one (60 mg) and phenylhydrazine (28 mg, 0.259 mmol) in acetonitrile (0.5 mL) was heated under microwave irradiation at 160° C. for 15 min and evaporated. The title compound was separated by flash chromatography on SiO2 (20 g, gradient heptane-ethyl acetate, the product came out with 50% ethyl acetate) to give 51 mg of a white solid, yield 66%. LC-MS (m/z) 412.2 (MH+); tR=1.48. 1H NMR (250 MHz, 70° C., DMSO-d6): 0.97 (t, J=7.3 Hz, 3H, Me of Et), 1.75-1.94 (m, 3H, CH2 of Et), 2.25 (s, 3H, Me), 4.98 (q (unresolved dt), J(d)=7 Hz, J(0=8.1 Hz, 1H, CH—NH), 6.68 (d, J=7.9 Hz, 2H, PhN), 6.83 (t, J=7.3 Hz, 1H, PhN), 7.14-7.51 (m, 9H), 7.69 (unres dt, J(t)=7.7 Hz, J(d)=1 Hz, 1H), 8.75 (s, 1H, NHPh), 8.8 (br. d, J=8.3 Hz, NHCO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:32]=1.CC(O)=[O:35].O.OO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[CH:16][C:17]3[CH:18]=[C:19]([OH:35])[CH:20]=[CH:21][CH:22]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:32]=1
Reactant: CC(=O)O
Reactant: CC1(C)OB(c2cccc(C=C3c4ccc(Cl)cc4CCc4cccnc43)c2)OC1(C)C
Agent: OO
Solvent: O
Solvent: C1CCOC1
Product: Oc1cccc(C=C2c3ccc(Cl)cc3CCc3cccnc32)c1

Procedure:
Mix 8-chloro-11-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (300 mg, 0.68 mmol), HOAc (1 mL), water (1 mL), THF (5 mL) and 30% H2O2 (mL). Stir the reaction at RT for 4 h. Quench with aqueous Na2S2O3 and extract the product into EtOAc. Dry (MgSO4) and concentrate to give 250 mg crude product. Purify by column chromatography (15% ethyl acetate/hexane) to give 66 mg 3-(8-chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidenemethyl)-phenol, Z-isomer as a white solid, mp 221.2° C. MS (ES) 334 (M+1), 332 (M−1). HPLC shows 99% purity.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH3:22]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: Cc1ccc(CC#N)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1cc(CC#N)ccc1C
Yield: 61.2 %

Procedure:
To a solution of (3-hydroxy-4-methylphenyl)-acetonitrile (1.7 g, 11.5 mmol) in acetone (100 ml), K2CO3 (7.9 g, 57.5 mmol) and 1-bromo butane (6.1 ml, 57.5 mmol) were added. The suspension was refluxed for 24 h and the solvent was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water and brine. The organic layer was dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude was purified by flash chromatography (petroleum ether:EtOAc 9.5:0.5) affording the title compound (1.43 g, 61% yield) as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:6][CH:7]=1.O.NN.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CC/C=C\c1cccc(Cl)c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCC/C=C\c1cccc(Cl)c1
Yield: 95 %

Procedure:
To a stirred suspension of (Z)-2-(4-(3-chlorophenyl)but-3-enyl)isoindoline-1,3-dione (8.4 g, 27 mmol) in ethanol (100 mL) at ambient temperature was added hydrazine monohydrate (65%, 2.6 mL, 54 mmol). The resulting mixture was stirred and heated to reflux, and a yellow solution formed upon attaining reflux. About 10 minutes after reflux began, a precipitate formed in the reaction mixture. After a total of 35 minutes at reflux, the precipitate nearly filled the flask, and the heat was removed. On reaching ambient temperature, the reaction mixture formed a solid mass. The mass was dissolved by adding of 2M sodium hydroxide (100 mL). The resulting solution was concentrated to remove most of the ethanol. The remaining cloudy mixture was extracted with ethyl acetate (100 mL). The aqueous layer turned into a gel and the organic layer was decanted away. The organic layer was washed with water (50 mL), then dried over sodium sulfate and concentrated to afford (Z)-4-(3-chlorophenyl)but-3-en-1-amine as a light brown oil (4.66 g, 95%).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=O)=O)=CC=1.[F:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([OH:25])=[CH:20][C:19]=1[N:26]1[C:30](=[O:31])[C:29]2[CH2:32][CH2:33][CH2:34][CH2:35][C:28]=2[C:27]1=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[F:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:20][C:19]=1[N:26]1[C:30](=[O:31])[C:29]2[CH2:32][CH2:33][CH2:34][CH2:35][C:28]=2[C:27]1=[O:36]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
Cyclopentyl p-toluenesulfonate (1.90 g, 8.11 mmol) was added to a solution of N-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.0 g, 6.76 mmol) and potassium carbonate (0.60 g, 4.34 mmol) in acetonitrile (50 ml), followed by stirring for 2 hours at 80° C. After completion of the reaction, 1N hydrochloric acid (20 ml) was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate (20 ml×3 times). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (5 ml) was added to the resulting pale yellow oily substance, and the precipitated N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a white solid (0.77 g 2.12 mmol, 31.4% yield) was isolated by filtration. The spectral data and the like are as described in Example 1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]#[N:18]>C(#N)C.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#CCOc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
To a stirred solution of 4-iodo phenol (700 mg, 3.1 mmol) in acetonitrile (7 ml) was added K2CO3 (1.31 g, 9.5 mmol), followed by bromo acetonitrile (410 mg, 3.4 mmol) at 20-35° C. and the reaction mixture was stirred at 80° C. for 6 h. The progress of the reaction was monitored by TLC. After 6 h of stirring, the mixture was cooled to 20-35° C., diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 15% ethyl acetate/hexane as an eluent to get the desired compound as a pale yellow liquid (400 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 7.65 (dt, J=5.4, 2.9 Hz, 2H), 6.79-6.77 (m, 2H), 4.74 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[CH3:9][S:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH3:22])[C:14]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:12])=[O:11].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[C:14]([C:23]([O:25][CH3:26])=[O:24])[C:15]=2[CH3:22])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1O
Reactant: COC(=O)c1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)c1O
Yield: 61.7 %

Procedure:
1.12 g (0.01 mol) of 1-ethyl-5-hydroxypyrazole was dissolved in 30 ml of t-amyl alcohol, and 2.72 g (0.01 mol) of 4-methanesulfonyl-3-methoxycarbonyl-2-methylbenzoic acid, 2.27 g (0.011 mol) of N,N'-dicyclohexylcarbodiimide and 0.76 g (0.0055 mol) of anhydrous potassium carbonate were sequentially added thereto. The mixture was reacted at 80° C. for 6 hours under stirring. After completion of the reaction, t-amyl alcohol was distilled off under reduced pressure, and then water was added to the residue to dissolve the soluble component. The mixture was subjected to filtration to separate out the insolubles. The aqueous solution thus obtained was washed twice with chloroform, and then concentrated hydrochloric acid was added to adjust pH<1. The precipitated oil component was extracted with chloroform. The chloroform layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate Then, the solvent was distilled off under reduced pressure, and the residue thus obtained was recrystallized from water/ethanol to obtain 2.26 g of the desired product. (Yield: 62%, melting point: 150°-152° C.)