Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[NH:4][CH:3]=1.[CH3:15][C@@H:16]1[O:21][C@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.CCN(C(C)C)C(C)C>C(O)CO>[CH3:22][CH:20]1[CH2:19][N:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[C:5](=[O:14])[NH:4][CH:3]=2)[CH2:17][CH:16]([CH3:15])[O:21]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: COc1ccc2c(=O)[nH]cc(N3CC(C)OC(C)C3)c2c1
Yield: 48.5 %

Procedure:
To a solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (0.2 g, 0.787 mmol) and (2S,6R)-2,6-dimethylmorpholine (0.181 g, 1.574 mmol) in ethylene glycol (2.5 ml) was added DIPEA (0.412 ml, 2.361 mmol). The reaction was irradiated in microwave at 145° C. for 1.5 h. The reaction mixture was adsorbed on silica was purified by silica gel chromatography (30% ethyl acetate in pet ether) to get desired compound (0.11 g, 48.5%) as solid. MS: MS m/z 289.18 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][C:36]=1[F:37]>>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[F:37])[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccc(F)c(F)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)c(F)c3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,4-difluorophenol: ESMS m/e: 511.1 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:12])([F:11])[CH2:9][OH:10].F[C:14]1[C:15]([C:20]([OH:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1>O>[F:7][C:8]([F:12])([F:11])[CH2:9][O:10][C:14]1[C:15]([C:20]([OH:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ncccc1F
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ncccc1OCC(F)(F)F
Reaction time: 4 h
Yield: 49 %

Procedure:
Potassium tert-butoxide (954 mg, 8.51 mmol) was charged to a sealed tube with 2,2,2-trifluoroethanol (4 mL) and 3-fluoropyridine-2-carboxylic acid (400 mg, 2.84 mmol) and the mixture was heated to 130 C for 26 h, then to 150 C for 4 h, and then to 120 C for approximately 18 h. The mixture was diluted with water (6 mL) and washed with DCM (2×4 mL), which was then discarded. 1M HCl was added to bring the solution to pH 7 and the aqueous was extracted with DCM (2×4 mL). The extraction process was repeated as above at pH 5, 4 and 3. The combined organic extractions were dried over sodium sulfate and evaporated under vacuum to afford the title compound as a white solid (305 mg, 49%). Method B HPLC-MS: MH+ requires m/z=222. Found: m/z=222, Rt=0.73 min (100%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][N:14]=[C:15]=[S:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:14]([CH2:13][C:12]2[CH:17]=[CH:18][C:9]([F:8])=[CH:10][CH:11]=2)[C:15]1=[S:16])[CH3:2]
Reactant: Fc1ccc(CN=C=S)cc1
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(Cc2ccc(F)cc2)C1=S
Yield: 38.3 %

Procedure:
The title compound was prepared by the procedure described in Example 4 using 9.2 g of N-ethyl glycine, 8.4 g of 4-fluorobenzyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethyl acetate/hexane mixture. Title compound (4.85 g) was obtained as a white solid, m.p. 73°-76° C. Anal. Calcd. for. C12H13F N2O S: C, 57.12; H, 5.19; N, 11.10 Found: C, 56.97; H,5.15; N, 11.06. Mass spectrum (EI, M.+) m/z 252.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](N(C)C)=[O:10]>>[CH3:8][C:9]([C:4]1[CH:5]=[CH:6][C:1]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:2][CH:3]=1)=[O:10]
Reactant: CC(=O)N(C)C
Reactant: Oc1ccccc1
Product: CC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
4-Phenoxyacetophenone was prepared by refluxing 4-fluoroaceotone and phenol in DMAc for 16 hours. The solvent was removed under reduced pressure and the reside subjected to standard ethyl acetate/water work-up and the resulting material purified by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=O)[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:13]4[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45]>C(O)C>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45].[CH2:17]([N:14]1[C:13]2[CH:24]=[CH:25][CH:26]=[CH:27][C:12]=2[O:11][C:10]2=[C:5]3[C:6](=[N:8][C:9]2=[C:15]1[N:38]1[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]1)[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4]3)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c2Oc2ccccc2N1Cc1ccccc1
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: CN1CCN(C2=C3N=c4cc(Cl)ccc4=C3Oc3ccccc3N2Cc2ccccc2)CC1

Procedure:
In the same way as described in example 1, 3-chloro-7-benzyl-7H-indolo[3,2-b][1,5]benzoxazepine-6(5H)-one, phosphorous pentachloride and N-methyl piperazine were reacted. The product was purified by chromatography on neutral alumina and elution with 3% ethanol in ether. The yellow oil thus obtained was reacted with fumaric acid in hot ethanol and the salt recrystallized from ethanol for analysis, mp. 217°-8°.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:5]=[CH:4][N:3]=[CH:2]1.[N:19]1[C:27]2[C:22]3[C:23](=[CH:28][CH:29]=[CH:30][C:21]=3[C:20]=1S)[CH:24]=[CH:25][CH:26]=2>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:20]2[C:21]3[CH:30]=[CH:29][CH:28]=[C:23]4[C:22]=3[C:27](=[CH:26][CH:25]=[CH:24]4)[N:19]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCCCCCCCCCCCn1ccnc1
Reactant: SC1=Nc2cccc3cccc1c23
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NCCCCCCCCCCCCn1ccnc1)=N2

Procedure:
A mixture of 2.5 g of 12-(1H-imidazol-1-yl)dodecanamine, 1.9 g of benz[cd]indole-2-thiol, 3.4 g of mercuric acetate and 400 ml of ethanol was reacted as described in Example 1. The crude product was purified by dissolving it in chloroform and chromatographing it on a silica gel column, eluting with 10% methanol in chloroform giving 490 mg of the desired product, mp 95°-97° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1[O:13][C:14](=[O:16])[CH3:15])(=[O:3])[CH3:2].[O:17]=[C:18]1[CH:27]=[CH:26][C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][C:20]3([S:36][CH2:35][CH2:34][S:33]3)[C:19]1=2>C1(C)C(C)=CC=CC=1>[C:14]([O:13][CH:6]1[C:7]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:26]2[CH:27]1[C:18](=[O:17])[C:19]1[C:20]3([S:36][CH2:35][CH2:34][S:33]3)[CH2:21][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:23][C:24]=1[C:25]2=[O:28])(=[O:16])[CH3:15]
Reactant: COC(=O)C1CC2=C(C(=O)C=CC2=O)C2(C1)SCCS2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)C1CC2=C(C(=O)C3C(OC(C)=O)c4ccccc4C(OC(C)=O)C3C2=O)C2(C1)SCCS2
Yield: 62 %

Procedure:
A solution of 0.757 g (3.4 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 0.970 g (3.1 mmol) of methyl rac-1',2',3',4',5',8'-hexahydro-5',8'-dioxospiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylate [prepared as described in Example 2(A)] in 100 ml of dry xylene was stirred and heated under reflux under an atmosphere of nitrogen for 1 hour. The mixture was evaporated to dryness and the resulting brown oil was triturated with 10 ml of diethyl ether, cooled and filtered to give 1.02 g (61.5%) of methyl rac-1',2',3',4',5',5a',6',11',11a',12'-decahydro-6',11'-diacetoxy-5',12'-dioxospiro[1,3-dithiolane-2,4'-naphthacene]-2'-carboxylate in the form of a pale yellow solid of melting point 174°-175° C.
Reaction SMILES: CON(C)[C:4](=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1.[CH3:34][C:35]([CH3:39])=[CH:36][Mg]Br>C1COCC1>[CH3:34][C:35]([CH3:39])=[CH:36][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1)=[O:32]
Reactant: CC(C)=C[Mg]Br
Reactant: CON(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Solvent: C1CCOC1
Product: CC(C)=CC(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-methoxy-N-methyl-3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzamide (50 mg, 0.11 mmol) in THF (0.5 mL) at 0° C. was added 2-methylpropenylmagnesium bromide (1.1 mL, 0.55 mmol, 0.5 M in THF). The reaction mixture was allowed to stir at room temperature for 30 min. It was quenched with sat. NH4Cl solution (0.5 mL) and was extracted with EtOAc (3×2 mL). The combined organic layer was washed with brine, was dried over anhydrous Na2SO4, was filtered and was concentrated under reduced pressure to give a white solid, which was further purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give 3-methyl-1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)but-2-en-1-one (I-87) as an off white solid. 1H NMR (CDCl3) δ ppm: 2.01 (s, 3H), 2.20 (s, 3H), 6.14 (s, 1H), 6.71 (s, 1H), 6.95 (s, 1H), 6.99-7.02 (m, 5H), 7.11 (t, J=7.36 Hz, 1H), 7.26-7.28 (m, 2H), 7.34 (t, J=7.56 Hz, 2H), 7.40-7.53 (m, 2H), 7.65 (d, J=7 Hz, 1H), 7.86 (s, 1H), 8.32 (s, 1H); LCMS: m/e 437.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([CH2:12][CH3:13])[O:11][C:7]=2[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH3:17][C:18]1[C:22]([NH2:23])=[C:21]([CH3:24])[O:20][N:19]=1>>[CH3:17][C:18]1[C:22]([NH:23][C:14]([C:6]2[C:7]3[O:11][C:10]([CH2:12][CH3:13])=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:16])=[C:21]([CH3:24])[O:20][N:19]=1
Reactant: Cc1noc(C)c1N
Reactant: CCc1nc2c(OC)ccc(C(=O)O)c2o1
Product: CCc1nc2c(OC)ccc(C(=O)Nc3c(C)noc3C)c2o1
Yield: 64 %

Procedure:
Starting from 4-methoxy-2-ethylbenzooxazole-7-carboxylic acid (0.23 g) and 3,5-dimethylisoxazol-4-ylamine (0.1 g). Purification by column chromatography on silica eluting with ethyl acetate afforded the title compound as a cream solid (0.18 g).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[NH2:17][C:18]1[CH:23]=[C:22]([OH:24])[C:21]([CH3:25])=[CH:20][CH:19]=1.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[OH:24][C:22]1[CH:23]=[C:18]([NH:17][C:2]2[C:11]3[CH:10]=[C:9]4[N:12]=[CH:13][N:14]=[C:8]4[CH2:7][C:6]=3[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:19]=[CH:20][C:21]=1[CH3:25]
Reactant: Cc1ccc(N)cc1O
Reactant: N#Cc1cnc2c(c1Cl)C=C1N=CN=C1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: Cc1ccc(Nc2c(C#N)cnc3c2C=C2N=CN=C2C3)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A mixture of 0.15 g (0.66 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.1 g (0.78 mmol) of 5-amino-o-cresol and 0.075 g (0.66 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at reflux temperature for 1 hour, cooled to room temperature, poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water, diethyl ether, methylene chloride, tetrahydrofuran and dried in vacuo to yield 0.17 g of 8-(3-hydroxy-4-methyl-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as white solid, mp 257-260° C. (dec).
Reaction SMILES: O.[CH2:2]([CH:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:17](O)[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:2]([CH:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCO
Reactant: CCCCCCC1C(=O)CCC1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCC1C(=O)CCC1C(=O)OCC

Procedure:
In a 1 L flask, to which is attached a water separator under a reflux condenser, is placed a solution of 20 g of 2-n-hexyl-3-oxo-cyclopentanecarboxylic acid, 9,5 g of absolute ethanol and 1 g of p-toluenesulphonic acid in 500 ml of benzene. The reaction mixture is refluxed until no more water separates. The reaction mixture is then cooled and washed successively with water and sodium carbonate solution and dried over anhydrous sodium sulphate. The solvent is removed by distillation at atmospheric pressure and the residue is distilled through a short Vigreux column. Ethyl 2-n-hexyl-3-oxo-cyclopentanecarboxylate is collected at 102°C/0.25 mm, yield 19,5 g (86%), nD20 1.4535.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:19]=[CH:20][C:21]([N+:25]([O-])=O)=[C:22]([CH:24]=4)[NH2:23])=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.O.N>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:24]=[C:22]([NH2:23])[C:21]([NH2:25])=[CH:20][CH:19]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Sc2nnc3ccc(-c4ccc(F)cc4)nn23)ccc1[N+](=O)[O-]
Agent: N
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Sc2nnc3n2N=C(c2ccc(F)cc2)CC3)cc1N
Temperature: 20 °C
Reaction time: 1 h
Yield: 215.3 %

Procedure:
422 mg of zinc(0) are added to a solution of 240 mg of 5-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-2-nitroaniline in 13 cm3 of acetic acid and the resulting mixture is stirred for 1 h at 20° C. 30 cm3 of water are then added to the reaction mixture, which is changed to an alkaline medium by adding 16 cm3 of an aqueous solution of ammonia at 28%. The mixture obtained is extracted with ethyl acetate. The resulting organic phase is washed successively with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride and is then dried over magnesium sulphate, filtered and evaporated to dryness. The residue is made into a paste in ether, filtered, and then dried under vacuum at 20° C. 479 mg of 4-{[6-(4-fluorophenyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}benzene-1,2-diamine are thus obtained, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH2:19]([O:18][C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][CH:14]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 56.8 %

Procedure:
10.0 g (51.8 millimoles) of 3-(p-aminobenzoyl)propionic acid, 6.7 g (61.7 millimoles) of ethyl chloroformate and 100 ml of absolute tetrahydrofuran are refluxed for 10 hours. The product is filtered off at 10° C., washed with water and recrystallized from dimethylformamide/water. 7.8 g (57% of theory) of 3-(p-ethoxycarbonylaminobenzoyl)-propionic acid are obtained as pale beige crystals, of melting point 206°-207° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1I.C([Sn](CCCC)(CCCC)[C:27]1[O:31][N:30]=[C:29]([CH3:32])[CH:28]=1)CCC>O1CCOCC1.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>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1[C:27]1[O:31][N:30]=[C:29]([CH3:32])[CH:28]=1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4cc(C)no4)c(F)c3)C(=O)O2)nn1
Temperature: 100 °C
Yield: 88.3 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (Intermediate 2, 2.08 g, 5.20 mmol) was dissolved in anhydrous 1,4-dioxane (10 ml) and degassed and placed under argon. Bis(triphenylphospine)palladium(II) chloride (0.145 g, 0.210 mmol) was added followed by dropwise addition of 5-(tributylstannyl)-3-methylisoxazole (2.41 g, 6.50 mmol) (Sakamoto, T. et al., Tetrahedron, 47, 28, 5111–5118) in 1,4-dioxane (2 ml). The reaction was degassed and heated at 100° C. for 48 hours. The solvent was removed under vacuum and the residue was dissolved in acetonitrile and washed with hexanes. The acetonitrile layer was concentrated to give a yellow solid (1.64 g) that was adsorbed onto silica gel and purified by flash chromatography using 10–20% acetone/dichloromethane. Relevant fractions were concentrated to give an off-white solid (1.50 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:12][C@@H:13]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15].[BH4-].[Na+].O>CO>[CH2:22]([N:19]1[CH2:18][CH2:17][N:16]([C:14](=[O:15])[C@@H:13]([NH:12][CH2:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:21][CH2:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C([C@H](Cc1ccccc1)NCc1ccc2[nH]ccc2c1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
In an inert atmosphere, indole-5-carboxaldehyde (108 mg, 0.75 mmol) and 2-amino-1-(4-benzyl-piperazin-1-yl)-(S)-3-phenyl-propan-1-one (162 mg, 0.50 mmol) were dissolved in dry MeOH (4.0 mL) and refluxed for 4 h. The reaction mixture was cooled to rt followed by slow addition of sodium borohydride (28 mg, 0.75 mmol). Stirring was continued for 1 h. Water (1 mL) was added to the reaction mixture followed by evaporation of the solvent under reduced pressure. The residue was dissolved in EtOAc (10 mL) and washed with sat. sodium hydrogencarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 200 mg (80%) of 1-(4-benzyl-piperazin-1-yl)-2-[(1H-indol-5-ylmethyl)-amino]-(S)-3-phenyl-propan-1-one. LC-MS: tR=0.65 min; [M+H]+=453.39.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18]OS(C)(=O)=O)[CH2:3]1.[NH2:24][NH2:25]>>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:24][NH2:25])[CH2:3]1
Reactant: NN
Reactant: CN1C[C@H](COS(C)(=O)=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Product: CN1C[C@H](CNN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 150 °C
Yield: 71 %

Procedure:
5 g (0.0146 moles) of 6-methyl-8β-mesyloxymethyl-ergoline are suspended in 25 ml of dry hydrazine distilled from sodium hydroxide. The suspension is refluxed under a nitrogen atmosphere on an oil bath heated to 150° C. for 20 minutes after the complete dissolution of the solids. In this operation atmospheric moisture should be excluded carefully. The mixture is cooled and allowed to stand in a refrigerator. The separated crystals are filtered off, washed with water, and then dried in vacuo. 2.8 g (71%) of 6-methyl-8β-hydrazinomethyl-ergoline are obtained; m.p.: 171°-172° C., [α]D20 =-62.8° (c=0.2, in tetrahydrofuran).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:23][CH3:24])[CH:4]=1.[CH2:25]([N:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]([OH:42])=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:25]([N:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]([O:42][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:23][CH3:24])[CH:4]=2)=[N:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 91.9 %

Procedure:
A mixture of 4-(4-chloromethyl-2-methoxyphenoxy)methyl-5-methyl-2-phenyl-1,3-oxazole (2.30 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate (3.10 g, yield 92%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 154-155° C.
Reaction SMILES: [ClH:1].FC1C=C([CH:29]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[O:34])[C:30](N)=[O:31])C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.[F:43][C:44]1[CH:45]=[C:46]([NH2:71])[CH:47]=[CH:48][C:49]=1[O:50][C:51]1[C:56]2=[C:57]([CH3:70])[C:58]([O:60][CH2:61][CH2:62][N:63]3[CH2:68][CH2:67][N:66]([CH3:69])[CH2:65][CH2:64]3)=[CH:59][N:55]2[N:54]=[CH:53][N:52]=1>>[ClH:1].[ClH:1].[F:43][C:44]1[CH:45]=[C:46]([NH:71][C:30](=[O:31])[CH2:29][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[O:34])[CH:47]=[CH:48][C:49]=1[O:50][C:51]1[C:56]2=[C:57]([CH3:70])[C:58]([O:60][CH2:61][CH2:62][N:63]3[CH2:64][CH2:65][N:66]([CH3:69])[CH2:67][CH2:68]3)=[CH:59][N:55]2[N:54]=[CH:53][N:52]=1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Yield: 46 %

Procedure:
Following a procedure similar to that for the synthesis of Compound D of Example 36, 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (60 mg, 0.15 mmol) was converted the title compound (30 mg, 46%) as a 2.HCl salt. 1H NMR (DMSO-d6) δ 10.63 (s, 1H), 10.37 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.80 (d, 1H), 7.61 (m, 2H), 7.40 (m, 2H), 7.16 (m, 2H), 4.42 (br s, 2H), 3.38-3.60 (m, 10H), 2.81 (s, 3H), 2.40 (s, 3H);). MS(ESI+) m/z 580.3 (M+H)+.