Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[C:10]([CH3:11])=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([CH3:26])[CH3:25]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:24]([CH3:26])[CH3:25])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]nc(C)c12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C(C)C
Yield: 53.1 %

Procedure:
Ethyl 6-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 g, 3.52 mmol) was suspended in acetonitrile (10 mL) and K2CO3 (0.728 g, 5.28 mmol) and 2-bromopropane (0.866 g, 7.04 mmol) was added to it. The reaction mixture was refluxed for overnight. On completion of reaction, acetonitrile was removed under reduced pressure and water added to it. Extraction was carried out using ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (0.61 g, 53.5%). Structure was confirmed by NOE.
Reaction SMILES: [Br-].[NH+]1C=CC=CC=1.C[O:9][C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[CH:11]=1.[O:25]([C:27]#[N:28])[Na].Cl>C1(C)C=CC=CC=1.O>[CH:23]1[CH:22]=[CH:21][C:13]2[N:14]([C:27]([NH2:28])=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10](=[O:9])[CH2:11][C:12]=2[CH:24]=1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#CO[Na]
Agent: Cl
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 89 °C
Yield: 58 %

Procedure:
The carbamoylation reaction was performed as in Example 1. After about 7–8 hours of stirring the carbamoylation reaction mixture (containing pyridinium bromide, 10-methoxy-5H-dibenz[b,f]azepine, water, toluene, and NaOCN) at room temperature (22° C.), the mixture was heated to 55–60° C., and 500 ml of 10% HCl was added drop-wise and carefully. The reaction mixture was warmed to reflux (89° C.) for 3–4 hours, and then worked up and purified as in Example 1. 32.8 g (58% yield) of crude oxcarbazepine was obtained. The crude afforded 24.9 g (44% overall yield) of pure oxcarbazepine.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][CH2:20][CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[N:9][N:10]([CH2:21][CH2:20][C:19]#[C:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nn[nH]n2)cc1
Reactant: OCCC#Cc1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C(#Cc1ccccn1)CCn1nnc(-c2ccccc2)n1
Temperature: 0 °C
Yield: 50.9 %

Procedure:
A mixture of 5-phenyl-2H-tetrazole (330 mg, 2.2 mmol), 4-(pyridin-2-yl)but-3-yn-1-ol (220 mg, 1.49 mmol) and triphenylphosphine polymer supported (750 mg, 2.2 mmol, loading 3mmol/g) were dissolved DCM (3 mL) and stirred at 0° C. Diisoprpylazodicarboxylate (452 mg, 2.2 mmol) was added dropwise, at 0° C. over a period of 30 min. The reaction mixture was then warmed to room temperature and stirred over night. The reaction mixture was filtered through celite and the cake was washed with DCM. The combined organic layers were washed with aqueous ammoniac, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (prepacked 25g silicagel column, DCM 100% as eluent) to afford 209 mg of 2-(4-(5-phenyl-2H-tetrazol-2-yl)but-1-ynyl)pyridine (Yield: 51%) as a pink powder (M.P.=71-73° C.).
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]([S:12]([C:15]2([CH2:23][CH2:24][Cl:25])[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH2:16]2)(=[O:14])=[O:13])([CH2:9][CH2:10][Cl:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.[Na+].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH2:4][C:5]([S:12]([C:15]2([CH2:23][CH2:24][Cl:25])[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH2:16]2)(=[O:14])=[O:13])([CH2:9][CH2:10][Cl:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COC1=CC=CC(CCCl)(S(=O)(=O)C2(CCCl)C=CC=C(OC)C2)C1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(C1(CCCl)C=CC=C(O)C1)C1(CCCl)C=CC=C(O)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
To 6 (8.95 mmol, 2.1 g) in dry DCM (50 cm3) was added 1M BBr3 (27 mmol, 27 cm3 ) in DCM at 0° C. The solution was allowed to reach 20° C. over night, poured into ice water (100 cm3) and stirred for 1.5 h. The aqueous layer was saturated with NaCl and extracted with DCM. The combined organic layers were dried over MgSO4. Filtration and removal of the solvent gave 7 as a white solid (7.8 mmol, 1.72 g, 87%). An analytical sample was obtained by recrystallisation from DCM (mp: 107.6° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:22])[CH3:21]
Reactant: COC(=O)c1cc(N)ccc1Br
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(C)=O)ccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Methyl 5-amino-2-bromobenzoate (Reference Compound No. 1-(1), 21.0 g, 91.2 mmol) and triethylamine (19.0 mL, 137 mmol) were dissolved in anhydrous dichloromethane (450 mL), acetyl chloride (13.0 mL, 182 mmol) was added dropwise over 30 minutes under ice cooling, and then the mixture was stirred at 0° C. for 2 hours. The reaction mixture was washed with water (200 mL, twice), saturated aqueous sodium hydrogen carbonate solution (200 mL, twice), and saturated brine (200 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was filtered with hexane-ethyl acetate (20:1) to give the titled reference compound (24.2 g) as a pale yellow solid. (Yield 98%)
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][N:4]([CH2:15][CH3:16])[N:3]=1.[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>N1C=CC=CC=1>[C:7]([C:6]1[C:2]([NH:1][S:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:29][C:19]3[N:20]=[C:21]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:22][C:18]=3[CH3:17])=[CH:32][CH:33]=2)(=[O:38])=[O:39])=[N:3][N:4]([CH2:15][CH3:16])[CH:5]=1)(=[O:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCn1cc(C(=O)c2ccccc2)c(N)n1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)c2ccccc2)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the title A compound, (3-amino-1-ethyl-1H-pyrazol-4-yl)-phenyl-methanone (0.035 g, 0.16 mmol) in pyridine at RT, is added 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride (0.06 g, 0.16 mmol) in pyridine. The solution is stirred at RT for 16 h. The reaction mixture is concentrated, the residue is taken up into ethyl acetate, washed with 1 N HCl, water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The crude product is chromatographed on silica gel using 50% ethyl acetate in hexanes to yield N-(4-benzoyl-1-ethyl-1H-pyrazol-3-yl)-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonamide as a solid: MS [m/z] 541.1 [M-1]−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[N:6][CH:7]=1.[C:17]([C:19]1[CH:20]=[C:21]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[C:27]([C:39]([F:42])([F:41])[F:40])[CH:26]=1)=[O:23])#[CH:18]>>[CH3:46][C:45]1[CH:44]=[CH:43][C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[C:27]([C:39]([F:40])([F:42])[F:41])[CH:26]=2)=[O:23])=[CH:20][C:19]=1[C:17]#[C:18][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cnc(-c2ccc(Br)cn2)[nH]1
Reactant: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(-c2ncc(C(F)(F)F)[nH]2)nc1

Procedure:
The title compound was prepared using 5-bromo-2-(5-trifluoromethyl-1H-imidazol-2-yl)pyridine and 3-ethynyl-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide as raw materials, according to the method described in Step 4 of Example 3.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C1COCC1>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: BrCc1ccccc1-c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2CN2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: 2-phenylbenzyl bromide (4{12}, 5 g, 20.2 mmol, 1 equiv.), piperazine (10.5 g, 121.4 mmol, 6 equiv.), THF (44.2 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{12} (3.92 g, 77%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.55 (dd, 1H, J=1.5, 7.0 Hz), 7.42-7.38 (m, 4H) 7.36-7.32 (m, 2H), 7.30 (dd, 1H, J=1.5, 7.0 Hz), 7.27 (dd, 1H, J=1.5, 7.0 Hz), 3.40 (s, 2H), 2.83 (t, 4H, J=5.0 Hz), 2.33 (br s, 4H), 1.58 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 142.6, 141.4, 135.5, 129.9, 129.8, 129.4, 127.8, 126.9, 126.7, 126.6, 60.3, 54.1, 46.1.
Reaction SMILES: C[O:2][C:3]1[CH2:21][CH2:20][C@H:19]2[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:18]2[CH2:17][CH2:16][C@@:13]2([CH2:14][CH3:15])[C@H:9]3[C@@H:10](OC(=O)C(C)(C)C)[CH2:11][C:12]2=[O:22])[CH:4]=1.[C-:30]#[C-:31].[Li+].[Li+]>>[C:30]([C@:12]1([OH:22])[CH:11]=[CH:10][C@H:9]2[C@H:8]3[C@H:18]([CH2:17][CH2:16][C@:13]12[CH2:14][CH3:15])[C@@H:19]1[C:5](=[CH:4][C:3](=[O:2])[CH2:21][CH2:20]1)[CH2:6][CH2:7]3)#[CH:31]
Reactant: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)C(C)(C)C)CC2=O
Reactant: [C-]#[C-]
Agent: [Li+]
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
Analogously to Example 1(b), 2.8 g of 3-methoxy-18-methyl-15α-trimethylacetoxy-3,5-estradien-17-one is reacted with lithium acetylide and worked up. Recrystallization from acetone/hexane yields 1.6 g of 17α-ethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one, melting point 197° C.
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.[O:31]=[C:32]1[NH:36][CH2:35][C:34](=[O:37])[N:33]1[CH2:38][CH2:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[C:43]([N+:49]([O-:51])=[O:50])[C:42]=1[O:52][CH3:53].C(=O)([O-])[O-].[K+].[K+].O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:45]/[C:44]2[CH:47]=[CH:48][C:41]([O:40][CH2:39][CH2:38][N:33]3[C:34](=[O:37])[CH2:35][NH:36][C:32]3=[O:31])=[C:42]([O:52][CH3:53])[C:43]=2[N+:49]([O-:51])=[O:50])=[N:3]1
Reactant: COc1c(OCCN2C(=O)CNC2=O)ccc(C=O)c1[N+](=O)[O-]
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1c(OCCN2C(=O)CNC2=O)ccc(/C=C/c2n[nH]c3ccccc23)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
(1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.12 g, 0.26 mmol), 4-[2-(2,5-dioxoimidazolidin-1-yl)ethoxy]-3-methoxy-2-nitrobenzaldehyde (0.08 g, 0.24 mmol) obtained in Step 1 and potassium carbonate (0.07 g, 0.47 mmol) were dissolved in methanol (3.0 mL), followed by stirring at room temperature for 1.0 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain (E)-3-(2-{4-[2-(1H-indazol-3-yl)vinyl]-2-methoxy-3-nitrophenoxy}ethyl)imidazolidine 2,4-dione (0.03 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[NH2:24][OH:25]>N1C=CC=CC=1>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[N:24][OH:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: NO
Reactant: O=C(O)COc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)COc1ccc(C(=NO)c2ccccc2F)c(Cl)c1Cl
Reaction time: 16 h

Procedure:
A mixture of 1.0 g of 2.3-dichloro-4-(2-fluorobenzoyl)phenoxyacetic acid and 1 g of hydroxylamine hydrochloride in 10 ml of pyridine is refluxed for 2 hours. Thereafter, the solvent is evaporated in vacuo and the residue is stirred for 16 hours with 5% hydrochloric acid. The product is filtered off and the collected solid is recrystallized from aqueous ethyl alcohol to give the product 2,3-dichloro-4-(2-fluorobenzohydroximoyl)phenoxyacetic acid having a melting point of 91° to 96° C.
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([C:29]([O:31][CH2:32]C)=[O:30])[C:8]2[CH2:9][CH2:10][N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)[C:12](=[O:19])[C:13]=2[C:14]=1[O:15]C(=O)C)(=O)C.C[O-].[Na+].Cl>CO.C1COCC1>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][N:11]1[CH2:10][CH2:9][C:8]2[C:7]([C:29]([O:31][CH3:32])=[O:30])=[N:6][C:5]([OH:4])=[C:14]([OH:15])[C:13]=2[C:12]1=[O:19]
Reactant: CCOC(=O)c1nc(OC(C)=O)c(OC(C)=O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3,4-bis(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (27.8 g, 58 mmol) was dissolved in 300 mL MeOH and treated with a 30% by weight solution of NaOMe in MeOH (41.8 mL, 232 mmol, 4 equivalents was sufficient to get the pH of the reaction to 9) for 5 hours at 40° C. LCMS showed the cleavage of the acetate groups was complete, a little transesterification was observed as well. The volume was reduced by half under vacuum and the mixture was diluted with THF (400 mL) and an additional 33 mL of NaOMe was added. The reaction was stirred at room temperature overnight and then warmed to 50° C. for four hours, when LCMS showed transesterification completed. The reaction was neutralized with 1N HCl and allowed to sit at room temperature overnight, then later acidified to pH 3 and extracted with CHCl3 several times. The organic layer was dried over Na2SO4 and evaporated to give a black oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:24])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O>CN(C=O)C>[CH3:24][N:4]([CH2:3][CH2:2][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[C:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:23])[O:9][CH2:8]2
Reactant: CN(CCCl)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCN1CCOCC1)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 110 °C

Procedure:
A mixture of 3-{5-[(2-chloro-ethyl)-methyl-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one (1.20 g, 3.52 mmol) and morpholine (3 ml, 34.4 mmol) in DMF (5 ml) was heated at 110° C. under nitrogen for 16 hours. The mixture was cooled to room temperature and was then poured into water (100 ml). The solid was filtered, washed with water and dried under vacuum to give a crude product. Purification of the crude product by silica gel column chromatography, eluted with a gradient of MeOH in CHCl3, resulted in 3-{5-[methyl-(2-morpholin-4-yl-ethyl)-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one as a yellow solid (0.57 g, 41%).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23](Br)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.[C:43]([Si:45]([CH3:48])([CH3:47])[CH3:46])#[CH:44]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:44]#[C:43][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc2[nH]cc(C(=O)N[C@@H](C(=O)N3CCC(C#N)CC3)C3CC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (0.50 g, 0.89 mmol) (5:1 mix of 5-Br and 5-Cl) in DMF (3 mL) were added sequentially triethylamine (0.50 mL, 3.56 mmol), ethynyltrimethylsilane (0.15 mL, 1.07 mmol), Pd(PPh3)2Cl2 (31.2 mg, 0.045 mmol), and copper (I) iodide (8.5 mg, 0.045 mmol). Upon the addition of CuI all solids dissolved. The reaction mixture was stirred at room temperature for 30 min then heated at 50° C. for 1 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/hexanes) to isolate 430 mg (83%) of 542-trimethylsilanyl-ethoxymethyl)-2-trimethylsilanylethynyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a brown foamy solid. NMR showed a trace of unreacted 5-Cl pyrrolopyrazine present.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][NH2:25])[CH3:20].O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([NH:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])=[O:16]
Reactant: CCN(CC)CCCN
Reactant: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)/C(=C/C=C/c1cc2ccccc2o1)OC
Yield: 18 %

Procedure:
A solution of (2Z,4E)-5-(benzofuran-2-yl)-2-methoxy-2,4-pentadienoic acid (122 mg, 0.5 mmol), 3-diethylaminopropylamine (65 mg, 0.5 mmol), 1-hydroxy-7-azabenzotriazole hydrate (65 mg, 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol) in DMF (2 ml) was stirred at RT overnight. After the same work-up described in example 3 the residue was chromatographed on silicagel (preparative TLC, EtOAc/MeOH/aq.NH3 8/2/1). The fraction collected was dried to give pure title compound (32 mg, O90 mmol, yield 18.0%) as pale brown crystals, m.p.=79°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:34][C:35]1[N:39]([CH3:40])[N:38]=[N:37][N:36]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:34][C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cn1nnnc1S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nnnc1SC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) in dry THF (30 mL) were added triphenylphosphine (2.0 g, 7.5 mmol) and 5-mercapto-1-methyl-1H-tetrazole (0.70 g, 6.0 mmol). To the mixture was added diisopropyl azodicarboxylate (1.2 mL, 6.0 mmol) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), which was washed with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, successively. The solvent was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (50 g, diethyl ether-hexane 1:1) to give the titled compound as a colorless oily substance. (1.11 g, 74%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13](F)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][C:8]=2[C:20]#[N:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27][OH:28]>>[CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:28][CH2:27][CH2:26][O:25][CH3:24])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][C:8]=2[C:20]#[N:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCO
Reactant: COc1cc2c(NC3CCCC3)c(C#N)cnc2cc1F
Agent: [H-]
Agent: [Na+]
Product: COCCOc1cc2ncc(C#N)c(NC3CCCC3)c2cc1OC
Temperature: 25 °C

Procedure:
A mixture of 4-cyclopentylamino-7-fluoro-6-methoxy-3-quinolinecarbonitrile (150 mg, 0.53 mmol) and sodium hydride (53 mg, 2.21 mmol) in 1.6 mL of 2-methoxyethanol is heated at reflux for 30 minutes, then cooled to room temperature. The reaction mixture is partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparative thin layer chromatography, eluting with 5% methanol in dichloromethane, followed by trituration with methanol and diethyl ether, provides 95 mg of 4-cyclopentylamino-6-methoxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 87-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([C:22]#[N:23])=[CH:18][NH:17][C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:29])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([C:22]#[N:23])=[CH:18][N:17]([CH3:29])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]cc(C#N)c2=O)c(F)cc1Cl
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c(C#N)cn(C)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[5-cyano-3,6-dihydro-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[5-cyano-3,6-dihydro-3-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 8.00 ppm (s, 1H), 7.83 ppm (d, 1H), 7.38 ppm (d, 1H), 5.25 ppm (m, 1H), 3.55 ppm (s, 3H), 1.37 ppm (2xd, 6H),
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.[CH2:10](O)[CH3:11]>S(=O)(=O)(O)O>[OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1
Reactant: CCO
Reactant: O=C(O)CC1(CO)CC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1(CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.0 g 2-[1-(hydroxymethyl)cyclopropyl]acetic acid (compound (13) was dissolved in 120 ml ethanol followed by addition of 6 drops of conc. sulfuric acid. The mixture was stirred at room temperature overnight. The mixture was concentrated partly to remove ˜40 ml ethanol and further stirred at room temperature (“rt”) for another day. The mixture was neutralized to pH˜7 (using ˜3 ml aq. saturated NaHCO3) and concentrated in vacuo. After re-dissolving in ethylacetate (200 ml), it was washed with brine (15 ml), dried and concentrated in vacuo to give a light-yellow oil (6.85 g).