Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([NH:16][CH:17]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH2:23]1)[C:13](O)=[O:14].P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O.O>[CH2:31]([O:30][C:28]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH:17]([NH:16][C@@H:12]2[C:13](=[O:14])[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:10][CH2:11]2)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:27][CH2:26]1)=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](CSc1ccccc1N)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2NC1=O
Yield: 65.5 %

Procedure:
In N,N-dimethylformamide (5 ml) is dissolved 3-(o-aminophenyl)thio-2(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]aminopropionic acid dihydrochloride (0.16 g), and diethyl phosphorocyanidate (0.3 ml) is added dropwise to the solution. To the mixture is added triethylamine (0.2 ml) and the reaction mixture is stirred under ice-cooling for 1 hour. The reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate (50 ml). The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silicagel column chromatography (hexane: acetone=2:1) to give 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (0.09 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3](OC)=O.C(O[CH:14]=[C:15](C#N)[C:16]#[N:17])C.C([N:22](CC)CC)C.C[O-].[Na+].CO>CO.C(O)(=O)C>[NH2:22][C:3]1[C:15]([C:16]#[N:17])=[CH:14][NH:1][C:2]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(N)C(=O)OC
Reactant: CCOC=C(C#N)C#N
Reactant: CCN(CC)CC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1[nH]cc(C#N)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
After dissolving dimethyl 2-aminomalonate (25.0 g) in methanol (300 mL), a solution of ethoxymethylene-malononitrile (16.6 g) and triethylamine (15.1 g) in methanol (50 mL) was added. The reaction mixture was stirred at room temperature for 18 hours and then cooled to 0° C., and a mixed solution of 28% sodium methoxide/methanol (31.5 g) and methanol (50 mL) was added dropwise thereto over a period of 10 minutes. The reaction mixture was stirred at room temperature for 49 hours and then cooled to 0° C., and acetic acid (10.3 g) was added. The solvent was distilled off under reduced pressure, ethyl acetate (200 mL) and water (200 mL) were added to the residue and extraction was performed with ethyl acetate. A saturated aqueous sodium bicarbonate solution was added to the organic layer until it exhibited a pH of 8, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (13.7 g, 61%) as a brown solid. The NMR and ESI/MS data for this compound are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6](C2C=CC(F)=CC=2Cl)[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][Br:12])=[O:4].[Br:26][C:27]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:28]=1C=O>>[Br:26][C:27]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:28]=1[C@H:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH2:11][Br:12])[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: O=Cc1cccc(F)c1Br
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1cccc(F)c1Br

Procedure:
Methyl (4R)-4-(2-bromo-3-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 94a was prepared in analogy to compound C with procedures shown in Example 1 by using 2-bromo-3-fluorobenzaldehyde instead of 2-chloro-4-fluoro-benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:25][C:26](Br)=[O:27].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][N:9]2[CH2:25][C:26]([NH:33][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[F:29])=[O:27])=[CH:22][CH:23]=1
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1F
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2F)cc1

Procedure:
prepared by reaction of 1-(4-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with 2-fluoro-benzylamine
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[N:8]=2)[CH2:3]1.C(N(CC)CC)C.Cl[C:33]([O:35][C@H:36]1[CH2:40][CH2:39][O:38][CH2:37]1)=[O:34]>C(Cl)Cl>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:33](=[O:34])[O:35][C@H:36]3[CH2:40][CH2:39][O:38][CH2:37]3)[CH2:3]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (907.2 mg, 2.16 mmol) was added 4 mL of 1:1 TFA:CH2Cl2. The mixture was stirred at room temperature for 5 hours. The reaction was diluted with a solution of saturated aqueous NaHCO3 and CH2Cl2. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to give 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol. To this free amine (640 mg, 2 mmol) was added 8 ml of CH2Cl2 and triethylamine (335 μL, 2.4 mmol). After cooling the mixture to 0° C., (S)-tetrahydrofuran-3-yl chloroformate (271 mg, 1.8 mmol) was added, and the reaction was allowed to stir for 30 minutes. Purification on silica gel using 30-100% ethyl acetate/hexanes gave (S)-tetrahydrofuran-3-yl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. 1H NMR (400 MHz, CDCl3) δ 14.8 (bs, 1H), 8.34 (d, J=6.4 Hz, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.48 (bs, 1H), 7.27 (m, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.82 (t, J=7.5 Hz, 1H), 5.21 (s, 1H), 5.06 (s, 1H), 4.37 (s, 1H), 4.15 (m, 1H), 4.02 (s, 1H), 3.97 (d, J=5.6 Hz, 1H), 3.87-3.77 (m, 5H), 2.42 (s, 3H), 2.24 (t, J=6.0 Hz, 1H), 2.15-2.06 (m, 1H), 1.98 (q, J=9.3 Hz, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:12][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH:7]=[CH:6][C:5]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: Nc1cc(Br)ccc1S(N)(=O)=O
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccc(S(N)(=O)=O)c(N)c1
Yield: 99.4 %

Procedure:
A mixture of 4-bromo-2-aminobenzenesulfonamide (140 mg, 0.56 mmol), 2-methoxyphenylboronic acid (106 mg, 0.70 mmol), Pd(PPh3)2Cl2 (20 mg, 5 mol %) in 1,2-dimethoxyethane (30 ml) and Na2CO3 (2M, 3 ml, 6 mmol) was refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO3 (20 ml) and extracted with EtOAc (2×40 ml). The organic layer was washed with brine (20 ml), dried (Na2SO,) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 155 mg (100%) of 2-amino-4-(2-methoxyphenyl)-benzenesulfonamide as colorless powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 219-221° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1ccc2ccnc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2ccnc(NCc3ccc(OC)cc3)c2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of ethyl 1-chloroisoquinoline-7-carboxylate (548 mg, 2.32 mmol) in N,N-dimethylformamide (9.3 mL) was added 4-methoxy-benzylamine (4.6 mL, 35 mmol) and potassium carbonate (5.14 g, 37.2 mmol). The reaction was heated to 70° C. and stirred overnight. The reaction was cooled to room temperature and was diluted with ethyl acetate and water. The layers were separated and the aqueous was extracted twice with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-35% ethyl acetate/heptanes) gave the title compound (430 mg, 55%) as a greenish oil. 1H NMR (400 MHz, CDCl3, δ): 8.49 (s, 1H), 8.16 (dd, J=8.6, 1.6 Hz, 1H), 8.09 (d, J=5.9 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.33-7.40 (m, 2H), 6.96 (d, J=5.9 Hz, 1H), 6.87-6.93 (m, 2H), 5.67 (br. s., 1H), 4.76 (d, J=5.1 Hz, 2H), 4.41 (q, J =7.2 Hz, 2H), 3.81 (s, 3H), 1.37-1.43 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][C:21]4[C:26]([N:27]=3)=[CH:25][CH:24]=[C:23]([C:28]3([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:30][CH2:29]3)[N:22]=4)=[C:15]([F:37])[CH:14]=2)[CH2:10][C@H:9]1[C:38]([OH:40])=[O:39])=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[F:37][C:15]1[CH:14]=[C:13]([C@@H:11]2[CH2:12][NH:8][C@H:9]([C:38]([OH:40])=[O:39])[CH2:10]2)[CH:18]=[CH:17][C:16]=1[C:19]1[S:20][C:21]2[C:26]([N:27]=1)=[CH:25][CH:24]=[C:23]([C:28]1([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:29][CH2:30]1)[N:22]=2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C[C@H]1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1C[C@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1

Procedure:
To a slurry of (2S,4R)-1-(tert-butoxycarbonyl)-4-(3-fluoro-4-(5-(1-phenyl-cyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-2-carboxylic acid (0.091 g, 0.16 mmol) in 2 mL DCM was added trifluoroacetic acid (0.13 mL, 1.6 mmol) to give a yellow solution. Upon completion the reaction mixture was concentrated in vacuo and the material was triturated with MTBE to give (2S,4R)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidine-2-carboxylic acid trifluoroacetic acid salt. MS (ESI) m/z: Calculated: 459.1; Observed: 459.8 (M++1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22-8.36 (m, 2 H), 7.57 (d, J=13.1 Hz, 1 H), 7.27-7.49 (m, 8 H), 7.05 (d, J=8.6 Hz, 1 H), 4.42 (dd, J=10.0, 7.6 Hz, 1 H), 3.59-3.81 (m, 2 H), 3.24-3.34 (m, 1 H), 2.72-2.85 (m, 1 H), 2.06-2.22 (m, 1 H), 1.62-1.74 (m, 2 H), 1.34-1.45 (m, 2 H)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][NH:6][C:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:21]=2)[N:12]=[C:11]([NH:31][C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][N:33]=2)[CH:10]=1)=[O:8].C(N(CC)CC)C.C1C[O:48][CH2:47][CH2:46]1>>[C:1]([NH:5][NH:6][C:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:21]=2)[N:12]=[C:11]([NH:31][CH:32]2[CH:36]=[C:35]([CH3:37])[NH:34][N:33]2[C:47](=[O:48])[CH3:46])[CH:10]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: Cc1cc(Nc2cc(C(=O)NN)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Reactant: CC(=O)Cl
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NNC(=O)c1cc(NC2C=C(C)NN2C(C)=O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Acetyl chloride (0.28 ml, 3.94 mmol) was added to a mixture of 6-hydrazide-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 77) (800 mg, 1.79 mmol) and triethylamine (0.6 ml, 4.13 mmol) in anhydrous THF (20 ml) at 0° C. The reaction was allowed to warm to ambient temperature and stirred for a further 1 hour. The volatiles were removed by evaporation and the residue triturated with water and collected by filtration to give the title compound (911 mg, 96%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>>[CH3:28][C:23]([CH3:29])([CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Reactant: COC(=O)C(C)(C)CCCCN
Product: COC(=O)C(C)(C)CCCCNc1cc(-c2ccccc2)c2ccccc2n1

Procedure:
A mixture of 3.2 g of 2-chloro-4-phenyl-quinoline (prepared according to the method of S. Kwon and K. Isagawa, Yoki Gosei Kagaku Shi 973,31, 313) and 5.9 g of methyl 6-amino-2,2-dimethylhexanoate is heated to 100° C. for 8 hours. After cooling, the residue is purified by chromatography on silica gel (eluent: 98:2 dichloromethane/methanol) to give methyl 2,2-dimethyl-6-[(4-phenyl-2-quinolyl)amino]hexanoate obtained as an oil.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: Nc1ccnc2ccccc12
Product: O=C(Nc1ccnc2ccccc12)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 4-aminoquinoline (Tyger), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc(N2CCN(C(=O)Nc3nc4ccc(OC)cc4nc3OC)CC2)cc1
Yield: 87 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 3.12-3.15 (m, 4H), 3.74-3.76 (m, 7H), 3.89 (s, 3H), 4.11 (s, 3H), 6.83-6.93 (m, 4H), 7.12-7.13 (m, 2H), 7.33 (s, 1H), 7.72-7.75 (m, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].Cl>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH:10]([CH3:11])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: CCC(=O)c1ccc(SC)cc1
Reactant: COC(=O)CBr
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CC(C)C(=O)c1ccc(SC)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of potassium hexamethylsilazane (0.158 mole) in toluene (254 ml) and THF (160 ml) at -78° C. was added dropwise the ketone from Step A of this Example (25.8 g) in THF (90 ml). The reaction mixture was stirred 30 minutes at -78° C. Methyl bromoacetate (16.2 ml) in THF (25 ml) was added dropwise. After stirring 1.5 hours at -78° C. the reaction mixture was poured into 1N HCl (400 ml). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4 and evaporated to give a yellow oil which was purified on a flash silica gel column (1 kg) using hexane/EtOAc (10:2) as eluant to give the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].O[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[C:23]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C.O>[C:18]([O:17][C:16]([NH:15][CH2:14][CH2:13][O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([O:6][CH3:23])=[O:5])=[C:2]([OH:1])[CH:10]=1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C([O-])c1ccc(O)cc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCNC(=O)OC(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
Commercially available starting materials 2,4-dihydroxybenzoate (1.04 g, 6.21 mmol), tert-butyl 2-hydroxyethylcarbamate (1.10 g, 6.82 mmol) and triphenylphosphine (1.8 g, 6.86 mmol) were dissolved in anhydrous THF (50 mL). To this solution was added diisopropyl azodicarboxylate (1.3 mL, 6.82 mmol) and the reaction was stirred for 18 h at room temperature. Water (200 mL) and ethyl acetate (200 mL) were added; the organic layer was separated, washed with water (2×200 mL), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silcagel column chromatography eluting with a gradient from 10%-50% ethyl acetate in hexane. Fractions containing the pure desired product were combined and solvent was removed under reduced pressure to produce a white solid (1.09 g, 56%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:26])[CH2:6]1)[C@:19]1([CH3:20])[C:14](=[C:15]([CH3:25])[C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[C:27]1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C>COC(OC)(C)C.C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:26])[CH2:6]1)[C@:19]1([CH3:20])[C:14]([C:15]([CH3:25])=[C:16]([O:24][CH3:27])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(=O)O[C@H]1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CCC4=C(C)C(=O)CC[C@@]43C)[C@H]12
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC1=C(C)C2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reaction time: 6 h
Yield: 512.7 %

Procedure:
5.0 g of 15α-acetoxy-4-methylandrost-4-ene-3,17-dione is stirred at 80° C. in 40 ml of 2,2-dimethoxypropane with 500 mg of pyridinium 4-toluenesulfonate. After 6 hours, 1 ml of triethylamine is added thereto; the mixture is diluted with ethyl acetate, washed with water, dried, and concentrated under vacuum. The crude product is chromatographed on silica gel containing 2% triethylamine with a hexane-ethyl acetate gradient, thus obtaining 3.8 g of 15α-acetoxy-3-methoxy-4-methylandrosta-3,5-dien-17-one as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([NH:1][C:2]3[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(Cl)cc(NC2CCC3(CC2)OCCO3)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (5.0 g, 25 mmol) and 1,4-dioxaspiro[4.5]decan-8-one (5.86 g, 37.8 mmol) in dichloroethane (50 mL) was added acetic acid (9.0 g, 150 mmol) and the reaction mixture stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (15.9 g, 752 mmol) was added at 0° C. and the reaction stirred overnight at room temperature. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to afford the title compound (6.6 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH2:14][F:15])([CH2:12][F:13])[CH2:8][C@@H:7]2O.N12CCCN=C1CCCCC2.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:42]([C@H:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[O:10][C:9]([CH2:14][F:15])([CH2:12][F:13])[CH2:8]1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@H]1CC(CF)(CF)Oc2c(Cl)cccc21
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=N[C@@H]1CC(CF)(CF)Oc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of Example 2B (7.75 g, 31.2 mmol) and THF (116 mL) was cooled to <5° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.91 mL, 53.0 mmol) and diphenylphosphoryl azide (10.09 mL, 46.8 mmol) were added. The yellow slurry was warmed slowly to ambient temperature, becoming a brown solution. After 14 hours, the mixture was concentrated, diluted with MTBE (200 mL), and washed with 2N NaOH (50 mL×2), brine (50 mL), 2N HCl (50 mL×2), and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to give the title compound. This material was used without further purification in the next step.