Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10](C)[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1C=CC=CC=1>[CH2:32]([O:31][C:29]([N:10]1[CH2:11][CH2:12][C@@H:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=2)[C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: CN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Reaction time: 1 h

Procedure:
A mixture of 3.49 g of trans-4-(4-fluorophenoxy)-1-methyl-3-phenylpiperidine of Example 30, 2.53 g of anhydrous potassium carbonate, and 28 ml of dry benzene are treated all at once under a nitrogen atmosphere with 1.75 ml of ethyl chloroformate. After 1 hour at ambient temperature, the mixture is refluxed 18 hours, then cooled and partitioned between ether and water. The phases are separated and the aqueous phase is extracted with ether. The combined ether extracts are washed with 2 N HCl solution, then with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to a gum which eventually crystallizes to a solid of trans-1-ethoxycarbonyl-4(4-fluorophenoxy)-3-phenylpiperidine, m.p. s 78°, 80°-82.5° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[CH2:16][C@H:15]([CH2:17][O:18]S(C4C=CC(C)=CC=4)(=O)=O)[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg]>CO>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[CH2:14][C@H:15]([CH2:17][OH:18])[CH2:16]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3ccc(CN4CCCC4)cc3)C2)cc1
Agent: [Mg]
Solvent: CO
Product: OC[C@H]1C[C@H](c2ccc(CN3CCCC3)cc2)C1
Reaction time: 16 h

Procedure:
To a stirring solution of: trans-toluene-4-sulfonic acid 3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethyl ester (example 48) (0.5 g, 1.2 mmol) in methyl alcohol (12.5 mL) was added magnesium turning. After 16 hours the reaction turned from a colorless solutions to a milky white solution. The reaction was quenched by the addtion of 1 mL of an aqueous solution of 15% NaOH and water. The solids were filtered off through a plug of celiteand the aqueous layer was extracted with 3:1 CH3Cl:isopropyl alcohol. The combined organic layer were dried over MgSO4, filtered through a fritted funnel and concentrated under reduced pressure to yield the title compound (242 mg, 79% yield) as a colorless oil. This material was processed without further purification.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]3[CH:19]=[N:20][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][CH:23]=3)=[C:13]2[N:12]=[C:11]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:10]=1[C:36]#[N:37].CCN(C(C)C)C(C)C.[OH:47][C@H:48]([CH2:52][OH:53])[C:49](O)=[O:50].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH2:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]3[CH:19]=[N:20][C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)=[C:13]2[N:12]=[C:11]([CH:30]2[CH2:31][CH2:32][N:33]([C:49](=[O:50])[C@H:48]([OH:47])[CH2:52][OH:53])[CH2:34][CH2:35]2)[C:10]=1[C:36]#[N:37]
Reactant: N#Cc1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reactant: O=C(O)[C@H](O)CO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1c(C2CCN(C(=O)[C@H](O)CO)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile TFA salt (0.1 mmol), DIEA (87 μL, 0.5 mmol) in DMF (2 mL) was added a solution of (R)-2,3-dihydroxypropanoic acid (11 mg, 0.1 mmol), HOBt (14 mg, 0.1 mmol), EDCI (29 mg, 0.15 mmol) in DMF (1 mL). The reaction was stirred at rt for 2.5 hour and the mixture was directly purified by HPLC to furnish the title compound. LC/MS RT=2.86 min. Mass calculated for M+H 484.2, observed 484.3.
Reaction SMILES: [C:1]1([C:14]([OH:16])=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.OS1C2C=CC=CC=2N=C1.Cl.C(N=C=NCCCN(C)C)C.[N:39]1([C:44]2[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=2)[NH2:47])[CH:43]=[N:42][CH:41]=[N:40]1>ClCCl.CN(C)C1C=CN=CC=1>[N:39]1([C:44]2[CH:45]=[C:46]([NH:47][C:14]([C:1]3[C:13]4[NH:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:16])[CH:48]=[CH:49][CH:50]=2)[CH:43]=[N:42][CH:41]=[N:40]1
Reactant: Nc1cccc(-n2cncn2)c1
Reactant: O=C(O)c1cccc2c1[nH]c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(-n2cncn2)c1)c1cccc2c1[nH]c1ccccc12
Reaction time: 0.25 h
Yield: 41.6 %

Procedure:
To a suspension of 9H-carbazole-1-carboxylic acid (148 mg) and 1-hydroxybenzothiazole (114 mg) in dichloromethane (3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (201 mg) and the mixture was stirred for 15 minutes. After adding 3-(1,2,4-triazol-1-yl)aniline (123 mg) and 4-dimethylaminopyridine (128 mg), the mixture was stirred for 24 hours. The mixture was evaporated under reduced pressure and purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-[3-(1,2,4-triazol-1-yl)-phenyl]-9H-carbazole-1-carboxamide (103 mg, 41.5%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.I[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.[Cl-].[NH4+]>[Cu](I)I.CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:11]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cn[nH]c1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cnn(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2-methyl-1′H,2H-3,4′-bipyrazole (176 mg), 4-iodobenzotrifluoride (485 mg), copper iodide (45 mg), potassium carbonate (329 mg), trans-N,N′-dimethylcyclohexan-1,2-diamine (135 mg) and N,N-dimethylformamide (2.2 mL) was stirred at 100° C. for 16 hours. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and was then concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=9:1 to 1:1), so as to obtain the title compound (280 mg) in the form of a colorless solid.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18](=[O:21])[N:19]([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1.FC(F)(F)C(O)=O>C(OCC)(=O)C.CCCCCC>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18](=[O:21])[N:19]([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCC(=O)N2C
Yield: 85.2 %

Procedure:
Reaction of intermediate 16, ethyl 3-benzyloxy-9-methyl-4,8-dioxo-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidine-2-carboxylate, (0.413 g, 1.16 mmol) with trifluoroacetic acid (20 ml) as described in the preparation of intermediate 5 gave 0.264 g (85% yield) of the title ester as white crystals, mp 182° C. (ethyl acetate/hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.44 (3H, t, J=7.1 Hz, CH3), 2.80 (2H, t, J=6.8 Hz, CH2), 3.43 (3H, s, NCH3), 4.28 (2H, t, J=6.8 Hz, CH2), 4.46 (2H, q, J=7.1 Hz, OCH2), 10.48 (1H, s, OH). Anal. Calcd for C11H13N3O5: C, 49.43; H, 4.90; N, 15.72. Found: C, 49.39; H, 4.89; N, 15.75.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH2:24]([N:26]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28]([CH3:34])=[N:27]1)[CH3:25]>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:31]([C:29]3[C:28]([CH3:34])=[N:27][N:26]([CH2:24][CH3:25])[CH:30]=3)=[O:32])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: CCn1cc(C(=O)O)c(C)n1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: CCn1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(C)sc2-c2cccc(F)c2)c(C)n1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.79 min; [M+H]+=468.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CC1C=CC(S([CH2:20][N+:21]#[C-:22])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:22]=[N:21][CH:20]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1cccc(-c2cnco2)c1

Procedure:
5-(3-Bromo-phenyl)-oxazole VI-a was prepared as described for intermediate I-c using 3-Bromo-benzaldehyde (10 g, 54 mmol), TosMIC (12.7 g, 65 mmol) and K2CO3 (8.97 g) in MeOH to give the desired intermediate VI-a as a brownish solid (12.1 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.92 (s, 1H), 7.80 (s, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 7.29 (d, J=7.9 Hz, 1H).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:45])[N:33]=2)=[CH:28][C:27]=1[Cl:46]>O>[Cl:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:34]1[N:33]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][O:17][C:8]3[CH:9]=[CH:10][C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:7]=3[Cl:6])=[C:27]([Cl:46])[CH:28]=2)[N:36]([CH3:37])[N:35]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To 30 ml of N,N-dimethylformamide are added 2-chloro-4-trifluoromethyl phenol (0.29 g) and potassium carbonate (0.25 g) and 5-(4-bromomethyl-3-chlorophenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (0.60 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 1 hour. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with toluene. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.61 g of desired compound (melting point: 113.0°-114.0° C.).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:33]([C:36]5[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=5[F:43])(=[O:35])=[O:34])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4S(C3C=CC=CC=3)(=O)=O)=[N:12][CH:11]=2)[CH2:3]1.[OH-].[Na+]>C(O)(C)C>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:33]([C:36]5[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=5[F:43])(=[O:34])=[O:35])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][NH:19]4)=[N:12][CH:11]=2)[CH2:3]1
Reactant: COc1ncc(-c2cc(-c3ncc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1ncc(-c2cc(-c3ncc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (105 mg, 0.140 mmol) was suspended in isopropanol (2 ml) and 2M sodium hydroxide (aq) (0.699 ml, 1.399 mmol) added. The reaction mixture was stirred at RT for 2 h, the solvent removed under a stream of nitrogen and the residue dissolved in water (1 ml) and acidified to pH˜6 by the addition of 2M hydrogen chloride (aq) (a black precipitate formed). The suspension was extracted with dichloromethane (3×2 ml) and the combined organics dried to give a brown solid. This was combined with the black precipitate which remained insoluble in the extraction, dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (20 mg).
Reaction SMILES: BrN1C(=O)CCC1=O.[C:9]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[P:22]([O:27]C)([O:25][CH3:26])[O:23][CH3:24]>C(Cl)(Cl)(Cl)Cl>[C:12]([O:11][C:9]([NH:16][CH:17]([P:22]([O:25][CH3:26])([O:23][CH3:24])=[O:27])[C:18]([O:20][CH3:21])=[O:19])=[O:10])([CH3:14])([CH3:15])[CH3:13]
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Reactant: COP(OC)OC
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A quantity of 2.92 g (0.016 mol) of N-bromo succinimide is added to 2.82 g (0.015 mol) of N-Boc glycine, methyl ester in 230 mL of carbon tetrachloride. The mixture is heated at reflux with stirring for 1 hour, cooled to 0° C., and filtered. The filtrate is evaporated to dryness and the residue is dissolved in 30 mL of tetrahydrofuran. A quantity of 2.10 g (0.017 mol) of trimethyl phosphite is added and the solution is maintained at reflux for 18 hours. The solvent is evaporated and the product is purified by silica gel chromatography eluting with ethyl acetate; wt 2.80 g (63%);
Reaction SMILES: O.NN.[CH2:4]([C:8]1[O:12][N:11]=[C:10]([CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:9]=1)[CH2:5][CH2:6][CH3:7].C(O)C>C1COCC1>[CH2:4]([C:8]1[O:12][N:11]=[C:10]([CH2:13][NH2:14])[CH:9]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCc1cc(CN2C(=O)c3ccccc3C2=O)no1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCCc1cc(CN)no1
Yield: 86.1 %

Procedure:
A solution of hydrazine hydrate (888 mg, 15.1 mmol) in THF (5 mL) was added to a solution of 2-[(5-butylisoxazol-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (2.14 g, 7.53 mmol) in 2:1 ethanol:THF (60 mL), and the solution was heated at reflux gently for four hours. A precipitate formed and was removed by filtration and washed with THF. The filtrate was concentrated under reduced pressure to provide 1.0 g of (5-butylisoxazol-3-yl)methylamine as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH3:23])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2C2C=CC=CC=2)C2CCCCC2)CCCCC1.CC(C)([O-])C.[Na+].Cl.Br[C:57]1[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:23])[C:57]4[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: Brc1ccncc1
Reactant: CNCCCCOc1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(CCCCOc1ccc2c(ccn2-c2ccc(F)cc2)c1)c1ccncc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
A mixture of 30 mg (0.091 mmol) {4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methylamine, 2 mg (0.009 mmol) Pd(OAc)2, 7 mg (0.02 mmol) (dicyclohexylphosphino)-biphenyl, 44 mg (0.46 mmol) sodium tert-butoxide, and 20 mg (0.1 mmol) 4-bromopyridine hydrochloride in 1 ml of degassed toluene was stirred in a pressure tube at 120° C. during 16 hours. After cooling to room temperature the mixture was treated with 0.5M aqueous NaOH and extracted three times with Et2O. Drying of the combined organic layers with Na2SO4, evaporation of the solvent, and column chromatography on silica gel with EtOAc/NEt3 100:3 gave 30 mg (81%) of {4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-pyridin-4-yl-amine as a light yellow oil, MS: 390 (MH+). (In analogy to L. Buchwald et al. J. Org. Chem. 2000, 65, 1158-1174).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH:13](OCC)=[O:14]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][CH:13]=[O:14]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCOC=O
Product: COc1ccc(CNC=O)c(OC)c1
Reaction time: 18 h
Yield: 62.5 %

Procedure:
2,4-Dimethoxybenzylamine (2.00 mL, 12.3 mmol) and the ethyl formate (4.96 mL, 61.4 mmol) were stirred at rt. After 18 h, the reaction mixture was concentrated in vacuo. The resulting solid was washed with ether and collected by filtration to afford the product as an off-white solid (1.5 g, 59%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:31][CH3:32])#[N:2].[OH-:33].[Na+].Cl>CS(C)=O>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[O:31][CH3:32])(=[O:33])[NH2:2]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1C#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1C(N)=O
Reaction time: 2 h

Procedure:
After dissolving N-(4-[(7-cyano-6-methoxy-4-quinolyl)oxy]phenyl)-N′-(4-fluorophenyl)urea (43 mg) in 1.5 ml of dimethylsulfoxide at 80° C., a 5N aqueous NaOH solution was added thereto and the mixture was heated and stirred for 2 hours. The reaction solution was neutralized with 1N HCl and the precipitated crystals were filtered out and washed with ethanol to obtain 17 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[O:10][C:9]3[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:22]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[C:25]=2[CH:24]=[CH:23]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH:22]1[C:30]2[C:25](=[C:26]([C:2]3[N:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:5]4[O:10][C:9]5[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=5[C:6]=4[N:7]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1
Reactant: Cc1ccc2c(n1)oc1c(N3CCOCC3)nc(Cl)nc12
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2c(n1)oc1c(N3CCOCC3)nc(-c3cccc4[nH]ccc34)nc12
Temperature: 90 °C
Yield: 16 %

Procedure:
To a solution of 2-chloro-7-methyl-4-morpholin-4-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine, 18 (27 mg, 0.09 mmol, leg), indole-4-boronic acid (43 mg, 0.27 mmol, 3 eq) and PdCl2(PPh3)2 (12.4 mg, 0.02 mmol, 20 mol%) in a mixture of dioxane (2 mL) and H2O (1.0 mL) was added Na2CO3 (19 mg, 0.18 mmol, 2 eq) under Ar(g). The reaction mixture was then heated in a pressure tube for 18 h at 90° C. Once cooled down, the mixture was partitioned with H2O (10 mL) and extracted with CH2Cl2 (2×10 mL) and EtOAc (2×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by SCX-3 cartridge eluting with CH2Cl2/MeOH (1:0-0:1 then +1M NH3) followed by silica gel column chromatography with hexane/EtOAc (3:1-0:1) to yield N as a pale brown solid (5.4 mg, 16%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][N:34]([CH3:37])[C:33]2=[O:38])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@@H:40]1[C:71](=[O:72])[N:42]2[C:43]([C:55]([O:57][CH:58]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])=[C:44]([CH2:47][S:48][C:49]3[N:53]([CH3:54])[N:52]=[N:51][N:50]=3)[CH2:45][S:46][C@H:41]12.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][N:34]([CH3:37])[C:33]2=[O:38])/[C:27]([NH:39][C@@H:40]2[C:71](=[O:72])[N:42]3[C:43]([C:55]([O:57][CH:58]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)=[O:56])=[C:44]([CH2:47][S:48][C:49]4[N:53]([CH3:54])[N:52]=[N:51][N:50]=4)[CH2:45][S:46][C@H:41]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN1CCC(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1CCC(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4nnnn4C)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
1.5 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetic acid are dissolved in 50 ml of tetrahydrofuran, and 1.4 g of benzhydryl 7β-amino-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylate, 0.6 g of 1-hydroxybenzotriazole and 0.92 g of dicyclohexylcarbodiimide are added thereto. The mixture is stirred at room temperature for 2 hours. Then, the reaction mixture is treated in the same manner as described in Example 3-(1). 1.58 g of benzhydryl 7β-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetamido}-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylate are obtained.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15]>ClCCl>[OH:13][CH:10]1[CH2:11][CH2:12][N:8]([C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)=[O:21])[CH2:9]1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: OC1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2.22 g of triethylamine (20 mmol), followed by 1.74 g of pyrrolidin-3-ol (20 mmol), were added to a solution of 3.71 g of 3-nitrobenzoyl chloride (20 mmol) in 40 ml of dichloromethane cooled to 0° C. The reaction medium was stirred at ambient temperature for 2 hours and was then diluted with 50 ml of dichloromethane. The organic phase was washed with 50 ml of a 1 N hydrochloric acid solution and then with 50 ml of a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated. 3.78 g of (3-hydroxypyrrolidin-1-yl)-(3-nitrophenyl)methanone were obtained and used without purification in the next step. Yield=80%.