Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[NH2:25][C:26]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36](CC3C=CC=CC=3)CC3C=CC=CC=3)=[CH:32][CH:31]=2)[CH2:28][CH2:27]1.FC(F)(F)C([O-])=O>>[NH2:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C:26]2([NH:25][CH2:21][CH:20]([C:12]3[C:13]4[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=4[C:9]([OH:8])=[CH:10][CH:11]=3)[OH:24])[CH2:27][CH2:28]2)=[CH:35][CH:34]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: NC1(Cc2ccc(N(Cc3ccccc3)Cc3ccccc3)cc2)CC1
Agent: O=C([O-])C(F)(F)F
Product: Nc1ccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)cc1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 342 mg (1 mmol) [4-(1-amino-cyclopropylmethyl)-phenyl]-dibenzyl-amine. Yield: 49 mg (10%, trifluoroacetate); mass spectroscopy: [M+H]+=370.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][CH:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:6][O:5]1)([CH3:3])[CH3:2].[BH4-].[Na+]>CCO>[CH3:11][CH:10]([CH3:12])[CH2:9][C@H:7]([NH:8][CH2:4][CH:1]([CH3:3])[CH3:2])[CH2:6][OH:5]
Reactant: CC(C)CC1COC(C(C)C)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CN[C@H](CO)CC(C)C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of (4 g)-2-isopropyl-4-isobutyl-1,3-oxazolidine (223g, 1.3 mol) in EtOH (1.1 L) cooled to −13° C. with an ice/MeOH bath was added NaBH4 (70.3 g, 1.82 mol) in portions at such a rate that the reaction temp. did not exceed 10° C. (approximately 2 h). The reaction mixture was allowed to warm to room temp., stirred overnight, then filtered through a coarse sintered glass funnel. The resulting solids were washed with EtOH. The combined filtrate was concentrated under reduced pressure and the residue was treated with EtOAc (2 L) and water (1 L). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield (2S)-4-methyl-2-(isobutylamino)pentan-1-ol as a viscous pale yellow oil (192 g, 85%): 1H NMR (CDCl3) δ0.90-0.96 (m, 12H), 1.18-1.24 (m, 1H), 1.32-1.39 (m, 1H), 1.58-1.72 (m, 2H), 2.33 (dd, J=11.1, 7.0 Hz, 1H), 2.49 (dd, J=11.1, 7.0 Hz, 1H), 2.61-1.67 (m, 1H), 3.19 (dd, J=10.3, 6.2 Hz, 1H), 3.60 (dd, J=10.3, 6.2 Hz, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:36][CH2:37][CH2:38]Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:38][CH2:37][O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCOCc2ccccc2)CC1
Yield: 91 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (6 g) as a starting compound, potassium carbonate (10.1 g) and 2-benzyloxyethyl chloride (3 g) were reacted and treated in the same manner as in Example 199 to give 6.36 g of 4-amino-N-((1-(2-benzyloxyethyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide, m.p. 123°-125° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH:22]=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Mg]Br>C1COCC1.[Cl-].[NH4+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH:22]([OH:23])[CH3:24])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)C1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a stirred solution of 4-[3-(benzyloxy)-5-fluorophenyl]-4-formyl-3,4,5,6-tetrahydro-2H-pyran (1.08 g, 3.4 mmol) in THF (16 ml) at room temperature under a nitrogen atmosphere was added on 0.96M solution of methyl magnesium bromide (5.3 ml, 5.1 mmol) in a dropwise manner. The mixture was stirred overnight, diluted with saturated aqueous ammonium chloride (40 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with water (40 ml) and brine (40 ml), dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica-gel, 150 g, ethyl acetate in n-hexane as an eluent increasing the amount of ethyl acetate from 40% to 60%) afforded the titled compound as a colorless liquid (0.71 g, 63%).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[OH-].[Na+]>C1COCC1>[NH2:5][CH2:4][CH2:3][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:1]
Reactant: N#CCC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCC(O)c1ccccc1
Temperature: 25 °C

Procedure:
3-oxo-3-phenylpropanenitrile (30 g, 207 mmol) in dry THF (300 mL) drop-wise at 0° C. under nitrogen atmosphere. The mixture was warmed to 25° C. and then heated at 70° C. for 2 hours. After cooling to 0° C., a saturated solution of sodium hydroxide was added drop-wise and extracted with dichloromethane (200 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by column chromatography (methanol:dichloromethane, 1:10) to afford 3-amino-1-phenyl-propan-1-ol. (Yield 30 g, crude).
Reaction SMILES: [CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)[CH3:2].[C:14](=O)=[O:15].CC(C)=O.C(N1CCCCC1)=O.Cl>O1CCCC1>[CH2:1]([CH:3]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][C:5]1[CH:9]=[C:8]([CH:14]=[O:15])[S:7][CH:6]=1)[CH3:2]
Reactant: O=C=O
Reactant: CCCCC(CC)Cc1ccsc1
Agent: Cl
Agent: O=CN1CCCCC1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCCC(CC)Cc1csc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
3-(2-Ethylhexyl)-thiophene (19.6 g, 100 mmol) and anhydrous tetrahydrofuran (250 mL) were charge into a 500 ml flask. The solution was cooled to −78° C. with dry ice/acetone. N-butyl lithium (40 mL, 2.5 M in hexane, 100 mmol) was dropped into the solution. After addition, the reaction solution was warmed to room temperature and stirred for 30 min. Then, the solution was cooled to −78° C. again and 1-formylpiperidine (13.6 g, 120 mmol) was added in one shot. The reaction solution was allowed to warm slowly to room temperature and stirred at room temperature for overnight. The solution was acidified with hydrochloric acid (2 N) and then extracted with ether (2×100 mL). The organic extracts were combined and washed with distilled water (2×100 mL), dried over anhydrous magnesium sulfate and rotary evaporated to remove the solvent. The residue was run through a silica-gel column using ethyl acetate/hexanes (1/10, v/v, Rf=0.3) as the eluent to give a colorless liquid product (18.4 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.86 (s, 1H), 7.56 (s, 1H), 7.34 (s, 1H), 2.59 (d, 2H, J=6.8 Hz), 1.58 (m, 1H). 1.18-1.34 (m, 8H), 0.84 (t, 6H, J=7.2 Hz); (Note: contain about 5% of 3-substituted isomer).
Reaction SMILES: OC[C:3]1[S:4][S:5][C:6]([CH2:9][O:10][Si](C(C)(C)C)(C)C)=[CH:7][CH:8]=1.[CH3:18][N:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23](O)[CH:22]=1)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:18][N:19]([C:21]1[CH:22]=[C:23]([O:10][CH2:9][C:6]2[S:5][S:4][CH:3]=[CH:8][CH:7]=2)[CH:24]=[CH:25][CH:26]=1)[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Reactant: CN(C)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)c1cccc(OCC2=CC=CSS2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a stirred solution of 200 mg (0.688 mmol) of 3-(hydroxymethyl)-6-[(tert-butyldimethylsilyloxy)methyl]-1,2-dithiin (U.S. Ser. No. 08/212,096) in 2 mL dry THF was added a solution of 3--N,N-dimethylaminophenol (190 mg, 1.376 mmol) in 2 mL THF, followed by addition of (220 mg, 0.839 mmol) triphenylphosphine. The resulting solution was cooled to 0° C., then 140 μL (155 mg, 0.890 mmol) of diethylazodicarboxylate was added, and the reaction mixture was kept at 0°-5° C. for 3 h until TLC analysis showed the reaction to be complete. For isolation of the products the reaction mixture was chromatographed directly on silica gel column, using ethyl acetate-hexane, 1:3 to yield 3-[tert-butyldimethylsilyloxy)methyl]-6-[[3-(N,N-dimethylamino)-phenyloxy]methyl]-1,2-dithiin (115 mg, 41.1%); 1H-NMR (CDCl3) δ7.3 (bs, 1 H), 7.1 (bs, 1 H), 6.60 (d, J=2.4, 1 H), 6.52 (bd, J=7.27 1 H), 6.42 (d, J=6.0, 1 H), 6.34 (d, J=6.0, 1 H), 4.60 (s, 2 H), 4.26 (s, 2 H), 2.65 (s, 6 H), 0.88 (s, 9 H), 0.07 (s, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH:11]1[CH2:24][C:25]([O:27]C)=[O:26])=[O:9].CO.O.O.[OH-].[Li+]>C(OCC)(=O)C>[CH3:35][O:34][C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:31]=1[O:32][CH3:33])[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH:11]1[CH2:24][C:25]([OH:27])=[O:26])=[O:9]
Reactant: COC(=O)CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1cc(OC)c(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(OCC(=O)N2CCN(Cc3ccc(F)cc3)CC2CC(=O)O)cc(OC)c1OC
Yield: 30 %

Procedure:
To a solution of 1-((3,4,5-trimethoxyphenoxy)methyl)carbonyl-2-(methoxycarbonyl)methyl-4-(4-fluorobenzyl)piperazine (0.20 g, 0.42 mmol) in a methanol/water solution (20 mL, 3:1) was added lithium hydroxide, monohydrate (0.40 mL, 9.5 mmol). The resultant mixture was stirred at ambient temperature for 30 min. At that time HPLC analysis showed complete conversion had occurred. The mixture was poured into ethyl acetate and washed sequentially with an aqueous acetic acid/water solution (pH <4), water, and brine. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford 0.060 g of 1-((3,4,5-trimethoxyphenoxy)methyl)carbonyl-2-(carboxy)methyl-4-(4-fluorobenzyl)piperazine as a white solid; NMR (CDCl3) 7.4 (m, 2), 7.1 (m, 2), 6.2 (m, 2), 5.1 (m, 1), 4.7 (m, 3), 4.0 (m, 2), 3.8 (d, 9), 3.3-3.1 (m, 4), 2.6 (m, 2), 2.4 (m, 2) ppm, MS (ESI) 476.
Reaction SMILES: C(O[C:6]([N:8]([C:41](OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH:37]3[CH2:39][CH2:38]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1CC[CH2:50][CH2:49]1>>[CH:37]1([C:33]2[CH:34]=[C:35]([CH3:36])[C:30]([N:27]3[CH2:28][CH2:29][N:24]([C:22]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][C:17]5=[O:21])=[CH:15][C:10]=4[C:9]([N:8]4[CH2:41][CH2:50][CH2:49][CH2:6]4)=[O:40])=[O:23])[CH2:25][CH2:26]3)=[N:31][CH:32]=2)[CH2:38][CH2:39]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Reactant: C1CCNC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C(=O)N2CCCC2)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 814 and pyrrolidine (36 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (45 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:13]2[O:18][CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14]2)[NH:11][CH:12]=1.Cl>[Pd].CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)[NH:11][CH:12]=1
Reactant: Clc1ccccc1-c1c[nH]c(C2CN(Cc3ccccc3)CCO2)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Clc1ccccc1-c1c[nH]c(C2CNCCO2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.9 %

Procedure:
Palladium on carbon (10 wt %, 96 mg, 0.090 mmol) was added to a solution of 2-[4-(2-chlorophenyl)-1H-imidazol-2-yl]-4-(phenylmethyl)morpholine (320 mg, 0.904 mmol) and hydrochloric acid (36%, 0.382 mL, 4.52 mmol) in CH3OH (80 mL) under nitrogen, and the mixture was stirred under hydrogen at 25° C. for 1.5 hours. The reaction mixture was filtered, washed by CH3OH (150 mL), and concentrated to afford the title compound (250 mg) as a brown solid. LC-MS (ES) m/z=264 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[N+:19]([O-])([OH:21])=[O:20]>>[CH3:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To concentrated sulfuric acid (10 mL) at 0° C. was added concentrated nitric acid (10 mL) dropwise and the mixture was allowed to stir at 0° C. for 10 min. 2-Methyl-4-nitrobenzic acid (1.81 g, 10 mmol) was added and the mixture was allowed to stir at RT for 5 d. The mixture was poured into ice-cold water and the solid was removed by filtration and dried to give 2-methyl-4,5-dinitrobenzoic acid (1.93 g, 85%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M−H]−=225 at 3.10 min. 1H NMR (400 MHz, d6-DMSO): δ 8.53 (s, 1H), 8.26 (s, 1H), 2.71 (s, 3H).
Reaction SMILES: [CH2:1]([N:13]([CH2:31][CH2:32][C:33]([O:35][CH2:36]C)=[O:34])[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CCCC(OCC)=O)CCOC1C=CC(CCC(=O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:1]([N:13]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])=[CH:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(CCOc1ccc(CCC(O)C(F)(F)F)cc1)CCC(=O)OCC
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Product: CCCCCCCCCCCCN(CCOc1ccc(CCC(=O)C(F)(F)F)cc1)CCC(=O)OC
Yield: 69.8 %

Procedure:
3-[N-Dodecyl-N-2-[4-[3-hydroxy-4,4,4-trifluorobutyl]phenoxy]ethylamino]propanoic acid, ethyl ester (320 mg, 0.60 mmol) was oxidized as described in the preparation of 4-[N-dodecyl-N-[2-[4-(3-oxo-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester (Example 48) and afforded the title compound (216 mg, 68%) as a pale yellow oil.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[NH:24][C:23]2[C:25]3[C:7]=1[CH2:8][C@@H:9]1[C:18]([C:19]=3[CH:20]=[CH:21][CH:22]=2)=[CH:17][C@H:12](C(NN)=O)[CH2:11][N:10]1[CH3:26].C([O-])([O-])=O.[K+].[K+]>O.Cl>[NH2:1][C@H:12]1[CH:17]=[C:18]2[C@@H:9]([CH2:8][C:7]3[C:25]4[C:23](=[CH:22][CH:21]=[CH:20][C:19]2=4)[NH:24][C:6]=3[CH3:5])[N:10]([CH3:26])[CH2:11]1
Reactant: O=N[O-]
Reactant: Cc1[nH]c2cccc3c2c1C[C@@H]1C3=C[C@H](C(=O)NN)CN1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1[nH]c2cccc3c2c1C[C@@H]1C3=C[C@H](N)CN1C
Reaction time: 0.17 h

Procedure:
1.4 g sodium nitrite in 5 ml H2O are added dropwise within 10 minutes under ice-cooling and stirring to 6.8 g of the product of step (b) in 200 ml 0.2N HCl. The reaction mixture is stirred under ice-cooling for 15 minutes and added dropwise unter nitrogen to 100 ml refluxing 0.4N HCl within 15 minutes. Stirring is continued for 10 minutes. The mixture is then cooled, rendered alkaline with saturated K2CO3 solution and extracted about 7 times with 9:1 CH2Cl2 /l CH3OH, whereby the black residue remains in the aqueous phase. The organic phase is dried (Na2SO4), evaporated, the resulting foam is chromatographed on silica gel using 80:20:0.7 CH2Cl2 /CH3OH/NH3 to afford the heading compound as a brown resin (pure 8α-compound by NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][OH:11])[CH2:15][CH2:16]2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: OCCN1CCNCC1
Product: O=C(c1cc(Cl)ccn1)N1CCN(CCO)CC1

Procedure:
Using 4-chloropicolinic acid chloride and 4-(2-hydroxyethyl)piperazine instead of N-Boc-piperazine, amidation was carried out in the same manner as Step A in Example 1-D-199, to obtain (4-chloro-pyridin-2-yl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (282 mg, 0.52 mmol), and (4-chloro-pyridin-2-yl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone (175 mg, 0.65 mmol) instead of 4-chloropicolinic acid t-butylamide, amination was carried out in the same manner as Example 1-D-07, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone as a colorless solid (210 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-202) as a colorless powder (114 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22]C)=[O:20].Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl
Agent: Cl
Product: COC(=O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
1.0 g. of ethyl 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}butyrate is left to stand in 20 ml. of methanolic hydrochloric acid at room temperature overnight. The reaction mixture is then evaporated to dryness with toluene. Sodium carbonate and ether are added to the residue. The organic phase is dried over sodium sulfate and evaporated to dryness. Recrystallization of the residue from cyclohexane gave methyl 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}butyrate, m.p. 95°-96°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 150 °C
Yield: 28.9 %

Procedure:
To 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (80 mg, 0.216 mmol) in dioxane and water (4 mL/1 mL) was added phenylboronic acid (36 mg), Pd(PPh3)4 (25 mg) and K2CO3 (104 mg). The reaction mixture was heated to 150° C. for 20 minutes by microwave irradiation. The organic phase was separated, concentrated, and purified by HPLC to afford the title compound (23 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29](=[O:31])[CH3:30].[CH3:32][C:33]([OH:37])([C:35]#[CH:36])[CH3:34].C(N(CC)CC)C>[Cu]I>[F:27][C:25]1[CH:24]=[CH:23][C:22]([NH:28][C:29](=[O:31])[CH3:30])=[C:21]([C:36]#[C:35][C:33]([OH:37])([CH3:34])[CH3:32])[CH:26]=1
Reactant: CC(=O)Nc1ccc(F)cc1Br
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(F)cc1C#CC(C)(C)O
Temperature: 85 °C

Procedure:
0.32 g (1.2 mmol, purity 99%) triphenylphosphine, 0.085 g (0.12 mmol, purity 99%) bis-triphenylphosphine palladium dichloride, and 0.14 g (0.72 mmol, purity 98%) copper(I)iodide are added to a mixture of 56.8 g (0.24 mol, purity 98%) N-(2-bromo-4-fluorophenyl)acetamide, 30.9 g (0.264 mol, purity 98%) 2-methylbut-3-yn-2-ol and 121.4 g (1.2 mol) triethylamine and the mixture is heated for 6 hours while stirring at 85° C. The surplus triethylamine is distilled off in a vacuum, approximately 170 ml toluene is added, the same quantity of water is added, and the phases are separated at ˜70° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][C:9](=O)[C:8]=2[C:7]([CH3:21])=[CH:6]1)(=[O:4])=[O:3].[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl.O>C(O)C>[ClH:27].[NH:25]([N:26]=[C:9]1[CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:13]2[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]([CH3:21])[C:8]1=2)[C:22]([NH2:24])=[NH:23]
Reactant: N=C(N)NN
Reactant: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cn(S(C)(=O)=O)c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Reaction time: 12 h
Yield: 46.7 %

Procedure:
A mixture of 1-methanesulfonyl-3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.41 g), aminoguanidine hydrochloride (0.16 g), concentrated hydrochloric acid (0.068 ml), water (0.068 ml) and ethanol (30 ml) was refluxed for 20 minutes. The reaction solution was allowed to stand in a refrigerator for 12 hours, and precipitated crystals were filtered, which were washed with ethanol and recrystallized from water to give 4-guanidinoimino-1-methanesulfonyl-3-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 13) (0.25 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[CH:16]=2)=[CH:4][CH:3]=1.I[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]3[C:16]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc(I)n1
Reactant: Fc1ccc(-c2cn3ccncc3n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3cnccn23)n1
Temperature: 80 °C
Yield: 42 %

Procedure:
A mixture of 2-(4-fluorophenyl)imidazo[1,2-a]pyrazine (Preparation #2, 0.964 g, 4.52 mmol), 4-iodo-2-(methylthio)pyrimidine (Frontier, 2.28 g, 9.04 mmol), Cs2CO3 (2.21 g, 6.78 mmol), triphenylphosphine (0.474 g, 1.84 mmol), palladium acetate (0.203 g, 0.904 mmol), and DMF (10.5 mL) was heated at about 80° C. for about 13 h. The mixture was cooled to ambient temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting material was triturated with EtOAc and filtered to yield the title compound (0.640 g, 41%): LC/MS (Table 1, Method b) Rt=2.0 min; MS m/z: 338.4 (M+H)+.