Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:32](Br)[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].O>O1CCCC1>[O:34]=[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32][N:13]1[CH2:14][CH2:15][N:10]2[C:9](=[O:16])[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]2[CH2:12]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=C(CBr)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 65.6 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.10 g, 0.34 mmol) in tetrahydrofuran (2 mL) were sequentially added diisopropylethylamine (0.6 mL) and phenacyl bromide (0.10 g, 0.51 mmol), and the mixture was stirred at room temperature for 17 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1), hexane was added thereto, and powder was formed to obtain the title compound (92 mg, yield 66%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.CO.[BH4-].[Na+].CC(C)=O>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc2nc(Cl)c(CO)cc2c1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To the mixture of 2-chloro-6-methoxy-3-quinolinecarbaldehyde (3.1 g, 14 mmol) and methanol (10 ml), sodium borohydride (530 mg, 14 mmol) was added at 0° C. (an outer temperature), and the obtained reaction mixture was stirred at the same temperature for 30 minutes. Acetone was added to the reaction mixture at the same temperature, followed by the addition of water and ethyl acetate at the same temperature. The organic layer was separated and washed with saturated saline. The solvents were evaporated under reduced pressure from the organic layer, and then the obtained residue was purified with silica gel column chromatography (heptane:ethyl acetate=1:1), thereby obtaining the entitled compound (3.0 g, 98%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[O:9])=[CH:3][CH:2]=1.[H-].[Na+].C([O-])(=O)CC([O-])=O.[CH3:29][O:30][C:31]([C:33]1[S:45][C:36]2[N:37]=[C:38](S(C)(=O)=O)[N:39]=[CH:40][C:35]=2[CH:34]=1)=[O:32]>C1COCC1.C1COCC1.CN(C=O)C>[CH3:29][O:30][C:31]([C:33]1[S:45][C:36]2[N:37]=[C:38]([CH:10]([C:11](=[O:12])[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8](=[O:9])[NH:7][C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[N:39]=[CH:40][C:35]=2[CH:34]=1)=[O:32]
Reactant: COC(=O)c1cc2cnc(S(C)(=O)=O)nc2s1
Reactant: O=C(CC(=O)Nc1ccccc1)Nc1ccccc1
Agent: O=C([O-])CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cnc(C(C(=O)Nc3ccccc3)C(=O)Nc3ccccc3)nc2s1
Reaction time: 0.17 h

Procedure:
To a solution of malondianilide (102 mg, 0.40 mmol) in THF (2 mL) was added of NaH (16.3 mg, 60% wt. dispersion in mineral oil, 0.41 mmol). After 10 min, the malonate salt solution was added to a solution of 2-methanesulfonyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (100 mg, 0.367 mmol) in THF/DMF (2/0.5 mL). After 1 h, the reaction was quenched with sat. NH4Cl and extracted with EtOAc. The organic layer was washed with brine (1×), dried over MgSO4, filtered, and concentrated. The residue was triturated with EtOAc and H2O, and the solid was filtered.: ESIMS calcd 447 (W+H), found 447 M++H).
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:31]3[C:30]([Cl:32])=[N:29][CH:28]=[N:27][C:26]=3[N:25]([CH3:33])[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CCOCC>C1COCC1>[NH2:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:31]3[C:30]([Cl:32])=[N:29][CH:28]=[N:27][C:26]=3[N:25]([CH3:33])[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1
Reactant: Cn1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1cc(C(=O)c2cncc(N)c2)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of [5-(benzhydrylidene-amino)pyridin-3-yl]-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 229, 30 g, 0.066 mol) in THF (200 mL) was added aq. citric acid (200 mL), the mixture was stirred for 30 min at room temperature. Ether was added and the layers were separated. The aqueous layer was adjusted to pH7 by aqueous Na2CO3. Then the mixture was filtered. The filter cake was evaporated with toluene and the residue was washed with EtOAc (200 mL) to give the title compound as a brown solid in 95% yield, 18 g.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C)C=O>[CH:21]1([O:1][C:2]2[CH:9]=[CH:8][C:7]([N:10]3[CH:14]=[N:13][N:12]=[N:11]3)=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=Cc1cc(-n2cnnn2)ccc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(-n2cnnn2)ccc1OC1CCCC1

Procedure:
A mixture of 2-hydroxy-5tetrazol-1-yl-benzaldehyde (500 mg) and potassium carbonate (431 mg) in dimethylformamide (5 ml) at 20° was treated with cyclopentyl bromide (0.33 ml). After 24 h water (20 ml) was added and the mixture extracted with ethyl acetate (2×25 ml). The organics were washed with water (25 ml) and brine (25 ml) and dried (Na2SO4). Evaporation gave a yellow solid which was purified by FCC (ethyl acetate/cyclohexane (2:1)) to give the title compound, as a yellow solid (334 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccnc1Br
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
To a solution of 2-bromo-3-formylpyridine (2.51 g) in methanol (40 ml) was added, at room temperature, sodium borohydride (255 mg). The mixture was stirred for 15 minutes at the same temperature. The reaction mixture was concentrated, to which was added water, followed by subjecting the mixture to extraction. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), which was then concentrated to afford 2-bromo-3-hydroxymethylpyridine (2.40 g). To a mixture of this compound (2.40 g), iodomethane (5.44 g) and DMF (25 ml) was added, at room temperature, 60% sodium hydride (613 mg), and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was poured water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, which was dried (anhydrous sodium sulfate), followed by concentration. The residue was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to afford 2-bromo-3-methoxymethylpyridine (2.34 g) as a yellow liquid product.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3]([O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:4]
Reactant: CCCCCCCCO
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)CBr
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
Bromoacetyl bromide (20 g, 99.1 mmol) was added to a solution of 1-octanol (12.9 g, 99.1 mmol) and 10 ml of pyridine in 100 ml of methylene chloride at 0° C. After 10 minutes, the mixture was quenched with 100 ml of ice/water, and the aqueous layer was extracted with methylene chloride, and the combined organic layer was washed with 1N HCl (3×100ml) and brine. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and the product was distilled under high vacuum to afford 6 g of 1-octyl bromoacetate as an oil, b.p. 93° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:4][N:3]=1.[H][H]>[Pt](=O)=O.C(O)C>[NH2:3][C:2]([CH3:1])=[CH:6][C:5]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:4]
Reactant: Cc1cc(-c2ccc(F)cc2)on1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(N)=CC(=O)c1ccc(F)cc1

Procedure:
3-Methyl-5-(4-fluorophenyl)isoxazole (620 mg, 3.49 mmol) is introduced into 16 ml of ethanol, platinum(IV) oxide catalyst (62 mg) is added, and the mixture is then hydrogenated under atmospheric pressure hydrogen for 12 h. The catalyst is filtered off and the filtrate is concentrated. 573 mg (91% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.CO[CH:23](OC)[CH2:24][NH:25][S:26]([NH:29]C(=O)OCC)(=[O:28])=[O:27].ClCCCl.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][CH2:23][CH2:24][NH:25][S:26]([NH2:29])(=[O:28])=[O:27])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CCOC(=O)NS(=O)(=O)NCC(OC)OC
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 0 °C

Procedure:
A mixture of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (68 mg, 0.20 mmol; from Step D) and ethyl {[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (154 mg, 0.600 mmol, 3.0 equiv.) in 1,2-dichloroethane (2.50 mL, 31.7 mmol) was stirred at 0° C. To this mixture was added trifluoroacetic acid (1.00 mL, 13.0 mmol) and triethylsilane (105 μL, 0.66 mmol, 3.3 equiv.)=drop-wise. The reaction mixture was stirred at 0° C. for 3 h. HPLC indicated 97.5% conversion to the desired product. The reaction mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate to pH ˜8. The mixture was extracted in ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was stirred in a mixture of heptane and diethyl ether overnight. The solids were collected by filtration, washed with heptane to give the desired product (95 mg, 88%) as a crude off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.08 (m, 1H), 7.70 (m, 2H), 7.59 (t, 1H, J=8.7 Hz), 6.56 (s, 1H), 4.04 (d, 2H, J=7.2 Hz), 3.35 (m, 2H), 3.11 (m, 2H), 1.15 (t, 3H, J=7.2 Hz); C15H15BrFN7O7S (MW 536.29), LCMS (EI) m/e 536/538 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[CH3:15])=[O:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:33]([O:37][C:38]([NH:40][C@H:41]([CH:63]=O)[CH2:42][S:43][C:44]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>ClCCCl>[C:33]([O:37][C:38]([NH:40][C@@H:41]([CH2:42][S:43][C:44]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:63][NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[CH3:15])=[O:6])=[O:39])([CH3:34])([CH3:35])[CH3:36]
Reactant: Cc1cccc(NC(=O)c2cccc(N)c2)c1C
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cccc(NC(=O)c2cccc(NC[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)NC(=O)OC(C)(C)C)c2)c1C
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 2 (0.28 g) in 12 mL of 1,2-dichloroethane at 0° C. was added sodium triacetoxyborohydride (0.36 g) and N-t-butyloxycarbonyl-S-(triphenyl- methyl)cysteinal (0.35 g). The cooling bath was removed and the mixture was stirred for 4 h at 20° C. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was extracted with 50 mL each of 2% potassium hydrogen sulfate, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a foam. NMR (300 MHz, CDCl3) δ 8.17 (1H, b), 7.46-7.18 (15H, m), 6.60 (1H, m), 3.13(2H, m,), 2.45(3H, m), 2.30 (3H, s), 2.18 (3H, s), 1.42 (9H, s).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([N:22]1[C:26](=[O:27])[CH2:25][NH:24][C:23]1=[O:28])[CH:5]([CH3:21])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl>>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH:5]([CH3:21])[CH:4]([N:22]2[C:26](=[O:27])[CH2:25][NH:24][C:23]2=[O:28])[C:3]([OH:29])=[O:2])=[CH:14][CH:13]=1
Reactant: COC(=O)C(C(C)CCOc1ccc(-c2ccccc2)cc1)N1C(=O)CNC1=O
Agent: Cl
Product: CC(CCOc1ccc(-c2ccccc2)cc1)C(C(=O)O)N1C(=O)CNC1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
A mixture of the compound obtained in step b above (24b) (320 mg, 0.808 mmol) and 3 N HCl (15 mL) was stirred at 80° C. for 4 h. The reaction mixture was cooled down and then extracted with EtOAc. The combined organic layers were dried and concentrated; the crude product was purified by silica gel column chromatography which gave the title compound as colourless oil (96 mg, 31%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:11][C:12]3[CH:17]=[N:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:20][CH2:19]4)=[N:14][C:13]=3[N:29]=2)=[CH:5][CH:4]=1)=O.FC(F)(F)C(O)=O.[NH:43]1[CH2:48][CH2:47][CH:46]([C:49]2[NH:50][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)=[N:52][N:53]=2)[CH2:45][CH2:44]1.CCN(CC)CC.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:28][N:26]([CH3:27])[C:24]([N:21]1[CH2:20][CH2:19][N:18]([C:15]2[N:16]=[CH:17][C:12]3[CH:11]=[C:10]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][N:43]5[CH2:48][CH2:47][CH:46]([C:49]6[NH:50][C:51]([C:54]7[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=7)=[N:52][N:53]=6)[CH2:45][CH2:44]5)=[CH:8][CH:7]=4)=[N:29][C:13]=3[N:14]=2)[CH2:23][CH2:22]1)=[O:25]
Reactant: c1ccc(-c2nnc(C3CCNCC3)[nH]2)nc1
Reactant: CN(C)C(=O)N1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN(C)C(=O)N1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(CN5CCC(c6nnc(-c7ccccn7)[nH]6)CC5)cc4)nc3n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 4-[7-(4-formylphenyl)-6-phenylpyrido[2,3-d]pyrimidin-2-yl]-N,N-dimethylpiperazine-1-carboxamide (7-1) (136 mg, 0.292 mmol) in DMF (5 mL) was added 2-(5-piperidin-4-yl-4H-1,2,4-triazol-3-yl)pyridine trifluoroacetate (73 mg, 0.32 mmol) followed by Et3N (80 μL, 0.51 mmol), AcOH (91 μL, 1.5 mmol) and sodium triacetoxyborohydride (59 mg, 0.28 mmol). The reaction mixture was allowed to stir for 12 hr then diluted with EtOAc and washed with NaHCO3 (sat.), dried with MgSO4, filtered, and concentrated under reduced pressure. The oily residue was purified by reverse phase HPLC (Acetonitrile/0.1% TFA in water gradient) to afford the title compound. LRMS m/z (M+H) Calcd.: 680.3, found 680.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[CH2:13](Br)[CH3:14]>CC#N>[CH2:13]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)[CH3:14]
Reactant: CCBr
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: CC#N
Product: CCc1c[nH]c2cc(N)ccc12

Procedure:
3-Ethyl-1H-indol-6-ylamine (B-12) was synthesized following the general scheme above starting from 6-nitroindole and ethyl bromide. Overall yield (42%). HPLC ret. time 1.95 min, 10-99% CH3CN, 5 min run; ESI-MS 161.3 m/z (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: OCc1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)Cc1cccc(-c2cccc(CO)c2)c1
Temperature: 90 °C
Yield: 104.9 %

Procedure:
3-Hydroxymethylbenzeneboronic acid (1.8 g, 11.8 mmol), 3-bromophenylacetic acid (2.55 g, 11.8 mmol), tribasic potassium phosphate, (7.54 g, 35.5 mmol), DMF (55 ml), and water (20 ml) were degassed under nitrogen in a 250 ml flask fitted with a reflux condenser. Bis[triphenylphosphine]palladium(II) chloride (0.17 g, 0.24 mmol) was added. The mixture was degassed under nitrogen, and heated at 90° C. overnight, then acidified with 2N HCl, mixed with brine (15 ml), and extracted with methylene chloride (3×15 ml). The organic materials were combined, dried (MgSO4), then concentrated under reduced pressure which gave 3.0 g of 3-(3-hydroxymethylphenyl)phenyl acetic acid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2].Cl[C:13]1[N:18]=[N:17][C:16]([C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([N:3]([C:13]1[N:18]=[N:17][C:16]([C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2]
Reactant: CCNCc1ccccc1N
Reactant: NC(=O)c1ccc(Cl)nn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccc1N)c1ccc(C(N)=O)nn1
Reaction time: 24 h
Yield: 39.2 %

Procedure:
N-Ethyl-N-(2-aminobenzyl)amine (707 mg, 4.7 mmol) in DMF (11 ml) was treated with 6-chloropyridazin-3-amide (4.7 mmol) followed by diisopropylethylamine (15.4 mol) and the reaction stirred at 140° under argon for 24 hours. The reaction was evaporated in vacuo (cold-finger) and the residue partitioned between water and ethyl acetate. The combined organic extracts were dried and evaporated to give a brown gum. The gum was purified by medium pressure chromatography to give 6-(N-ethyl-N-(2-aminobenzyl)amino)-pyridazine-3-carboxamide (500 mg, 30%).
Reaction SMILES: [OH:1][C:2]([C@H:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=O.C(C1C=CC([C@H](C)C(Cl)=O)=CC=1)C(C)C.C(Cl)(=O)C(Cl)=O.[Cl-].[NH3:38]>>[CH2:10]([C:9]1[CH:14]=[CH:15][C:6]([C@H:4]([CH3:5])[C:2]([NH2:38])=[O:1])=[CH:7][CH:8]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: N
Reactant: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Agent: CC(C)Cc1ccc([C@H](C)C(=O)Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Product: CC(C)Cc1ccc([C@H](C)C(N)=O)cc1

Procedure:
The above hydrolysis procedure gives about 2% racemization demonstrated by: (1) converting a sample of (S)-(+)-ibuprofen (98.6% S enantiomer by HPLC) to (S)-(+)-2-(4-isobutylphenyl)propanoyl chloride with oxalyl chloride; (2) treating the chloride with ammonia to obtain (S)-(+)-2-(4-isobutylphenyl)propionamide; and (3) hydrolyzing the amide as described above to regenerate (S)-(+)-ibuprofen (96.6% S enantiomer by HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8](Br)=[N:9][CH:10]=1)=[O:4].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)nc1
Reactant: C1CNCCN1
Solvent: CC#N
Product: COC(=O)c1ccc(N2CCNCC2)nc1
Yield: 55.6 %

Procedure:
A mixture of 2-bromopyridine-5-carboxylic acid methyl ester (1.40 g, 6.5 mmol) and piperazine (5.59 g, 65 mmol) was dissolved in acetonitrile (50 ml) and heated at reflux temperature for 2.5 h. The reaction mixture was concentrated in vacuo, dissolved in dichloromethane (50 ml) and extracted with water (3×50 ml). The organic solution was dried (MgSO4) and evaporated in vacuo, affording 0.80 g (56%) of 2-(1-piperazinyl)-5-pyridinecarboxylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:14]1([CH3:19])[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2ccccc12
Reactant: Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1Nc1cccc2ccccc12
Temperature: 100 °C
Yield: 91.5 %

Procedure:
A mixture of 1-aminonaphthalene (7.15 g, 50 mmol), 1-bromo-2-methylbenzene (8.5 g, 50 mmol), Pd(dppf)Cl2 (1.0 g, 1.36 mmol), sodium tert-butoxide (9.6 g, 0.1 mol) in toluene (120 mL) was degassed and heated at about 100° C. overnight. The resulting mixture was worked up with ethyl acetate/brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 9:1. After removal of solvents, an oil (Compound 20) was obtained, 10.2 g in 91.5% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19].[OH2:23]>ClCCl>[S:18]([OH:23])(=[O:20])(=[O:19])[CH3:21].[OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1
Reactant: O
Reactant: CS(=O)(=O)Cl
Agent: O=C1CCC(CCO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 15.25 g (107.24 mmol) 4-(2-hydroxyethyl)cyclohexanone in 115 mL of dichloromethane cooled at a temperature close to 0° C., is added 18 mL (129.5 mmol) of triethylamine, then 9.25 mL (119.50 mmol) of mesyl chloride. The mixture is stirred for two hours at room temperature. Water (120 mL) is added. The organic phase is separated by decantation, washed with a saturated aqueous solution of sodium hydrogenocarbonate (100 mL), dried over magnesium sulfate and concentrated under reduced pressure to give 28 g of 4-(2-hydroxyethyl)cyclohexanone mesylate used without further purification in the next step.