Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][C:17](=[O:26])/[CH:18]=[CH:19]/[C:20]2[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=2)=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.Cl>O1CCOCC1>[NH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[NH:16][C:17](=[O:26])/[CH:18]=[CH:19]/[C:20]1[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=1
Reactant: Cn1cc(/C=C/C(=O)Nc2ccc(F)cc2NC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(/C=C/C(=O)Nc2ccc(F)cc2N)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
(E)-tert-butyl (5-fluoro-2-(3-(1-methyl-1H-pyrazol-4-yl)acrylamido)phenyl)carbamate (0.15 g, 0.42 mmol) was dissolved in dioxane (4 mL). A 4M solution of HCl in dioxane (4 mL) was added and the mixture was stirred at room temperature for 3 h. Salt precipitation was observed. The reaction mixture was then diluted with diethyl ether (20 mL) and the crude hydrochloride salt was filtered. It was stirred with saturated sodium bicarbonate (excess) and filtered. The precipitate was washed with water and vacuum dried. (E)-N-(2-amino-4-fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)acrylamide (73 mg) was obtained as an off-white solid. 1H NMR (CD3OD) δ: 7.88 (s, 1H), 7.77 (s, 1H), 7.53 (d, J=15.7 Hz, 1H), 7.12 (dd, J=8.5, 5.9 Hz, 1H), 6.54 (d, J=15.9 Hz, 1H), 6.55 (dd, J=10.5, 3.0 Hz, 1H), 6.39 (td, J=8.5, 2.7 Hz, 1H), 3.90 (s, 4H); ES+(M+H)+261.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>CC#N>[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:5][CH3:3])=[O:14]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: CC#N
Product: CNC(=O)c1cccnc1Cl
Temperature: 23 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
Methanamine (0.425 mL, 3.41 mmol) and triethylamine (0.792 mL, 5.68 mmol) were dissolved in CH3CN (14.2 mL) at 23° C. 2-Chloronicotinoyl chloride (500 mg, 2.84 mmol) was added and the reaction mixture was stirred at 23° C. for 16 h. The solvent was removed by rotary evaporation and the residue was partitioned between EtOAc (20 mL) and sat. aq. NaHCO3 (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phases were dried over MgSO4 and concentrated. Trituration of the resulting solid with 5% EtOAc-hexane provided the desired product as a white powder (153.2 mg, 31%). 1H NMR (CD3OD) δ 8.43 (dd, 1H, J=5.09, 2.03 Hz), 7.88 (dd, 1H, J=7.63, 2.03 Hz), 7.45 (dd, 1H, J=7.38, 4.83 Hz), 2.91 (s, 3H); MS(ESI+) m/z 171.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:19]=[S:20])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:26]1([N:3]2[CH2:2][CH2:7][N:6]([CH2:12][CH2:13][CH2:14][NH:18][C:19]([NH:18][C:14]3[CH:13]=[C:12]([N:6]4[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]([CH3:25])=[C:5]4[C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:16][CH:15]=3)=[S:20])[CH2:5][CH2:4]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: c1ccccc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N=C=S)c1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(NC(=S)NCCCN2CCN(C3CCCCC3)CC2)c1
Yield: 92 %

Procedure:
1,4-Dihydro-2,6-dimethyl-4-(3-isothiocyanatophenyl)-3,5-pyrazinedicarboxylic acid, dimethyl ester (500 mg, 1.4 mmol) was refluxed with 4-cyclohexyl-1-piperazine-1-propanamine (345 mg, 1.5 mmol) in 8 mL of benzene for 2 hours. Chromatographic purification (on silica gel, 100% methylene chloride first, followed by 10% (v/v) methanol in methylene chloride) of the residue after concentration in vacuo gave the title compound as a yellow foam (752 mg, 92%); 1H-NMR (CDCl3) δ 7.63 (br, 1H), 7.11 (t, 1H, J=8.0 Hz), 6.85 (br, 1H), 6.72 (br, 1H), 6.60 (d, 1H, J=8.2 Hz), 6.56 (dd, 1H, J=8.3, 2.2 Hz), 6.45 (br, 1H), 3.75 (s, 6H), 3.65 (m, 2H), 2.40 (s, 6H), 2.31 (t, 2H, J=6.6 Hz), 2.20-2.60 (m, 8H), 2.16 (m, 1H), 1.50-1.95 (m, 7H), 1.00-1.30 (m, 5H); 13C-NMR (CDCl3) δ 165.9, 152.5, 149.2, 130.1, 112.0, 108.8, 63.6, 53.2, 51.9, 48.7, 29.0, 26.2, 25.8, 25.3, and 18.0.
Reaction SMILES: [Cl:1][C:2]1[C:25]([N:26]([C:28](=[O:41])[CH2:29][N:30]2C(=O)C3=CC=CC=C3C2=O)[CH3:27])=[CH:24][CH:23]=[C:22]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.O.NN>C(O)C>[NH2:30][CH2:29][C:28]([N:26]([C:25]1[C:2]([Cl:1])=[C:3]([C:22]([Cl:42])=[CH:23][CH:24]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH3:27])=[O:41]
Reactant: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Yield: 100.3 %

Procedure:
To a suspension of 8-[2,6-dichloro-3-(N-phthalimidoacetyl-N-methylamino)benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (1.91 g) in ethanol (19 ml) was added hydrazine monohydrate (318 mg), and the mixture was refluxed for 1 hour. After cooling, the resulting precipitates was filtered off. The filtrate was concentrated in vacuo, and the residue was dissolved in chloroform. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. The residue was pulverized with diisopropyl ether to give 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (1.5 g) as colorless amorphous.
Reaction SMILES: [ClH:1].O[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[S:9][CH2:10][C:11]([OH:13])=[O:12].O>[Cl-].[Na+].O>[Cl:1][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[S:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CS[C@@H]1CCCC[C@H]1O
Reactant: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CSC1CCCCC1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Concentrated hydrochloric acid (200 ml) was added to the compound of Example 10 (27.1 g, 0.13 mole) and the reaction mixture was stirred at room temperature for 20 hours. Water (100 ml) and brine (50 ml) were added to the reaction mixture. The reaction mixture was extracted three times with 175 ml of diethyl ether. The combined diethyl ether extracts were washed three times with 30 ml of water and dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography. The structure was supported by NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:24]2[C:28](=[O:29])[CH2:27][CH2:26][C:25]2=[O:30])[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2C(=O)CCC2=O)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following similar methods to those described in Preparation 356 starting from (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester and pyrrolidine-2,5-dione. 1H NMR (CDCl3): 7.37-7.01 (5H, m), 4.24-4.06 (1H, m), 3.89 (1H, d), 3.80-3.47 (4H, m), 3.22 (2H, d), 3.09-2.78 (1H, m), 2.70-2.55 (4H, m), 2.33 (1H, dd), 1.48 (9H, s), 1.19 (3H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:79])([CH3:78])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[C:12]([CH2:28][NH:29][C:30](=[O:75])[C@H:31]([CH3:74])[NH:32][C:33](=[O:73])[C@H:34]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[CH:64][CH:63]=1)[NH:35][C:36](=[O:60])[C@H:37]([C@H:56]([CH2:58][CH3:59])[CH3:57])[NH:38]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:11]([O:76][CH3:77])=[CH:10][CH:9]=3.C(NCC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:79])([CH3:78])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[C:12]([CH2:28][NH:29][C:30](=[O:75])[C@H:31]([CH3:74])[NH:32][C:33](=[O:73])[C@H:34]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][C:69]([CH3:70])([CH3:71])[CH3:72])=[CH:64][CH:63]=1)[NH:35][C:36](=[O:60])[C@H:37]([C@H:56]([CH2:58][CH3:59])[CH3:57])[NH2:38])[C:11]([O:76][CH3:77])=[CH:10][CH:9]=3
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)NCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](C)C(=O)NCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Yield: 85.3 %

Procedure:
A solution of 0.74 g (0.73 mmol) of benzyl 3,6-dimethoxy-9,9-dimethyl-5-[(N-(9H-fluoren-9-ylmethoxycarbonyl)-L-isoleucyl-O-tert-butyl-L-tyrosyl-L-alanyl)aminomethyl]xanthene-4-acetate in 7 ml of dimethylformamide was stirred at 0° for 1 hour in the presence of 0.7 ml of diethylamine. The reaction mixture was brought to dryness. The residue obtained was chromatographed over silica gel in chloroform/methanol, whereby 0.53 g of benzyl 3,6-dimethoxy-9,9-dimethyl-5-[(L-isoleucyl-O-tert-butyl-L-tyrosyl-L-alanyl)aminomethyl]xanthene-4-acetate was obtained; IR 3292, 2970, 1742, 1672, 1655, 1627, 1605, 1536, 1502, 1499 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl:27]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][C:17]=3[Cl:27])[CH:10]=[N:9]2)=[CH:25][CH:26]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)cn2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3Cl)cn2)cc1
Yield: 84.1 %

Procedure:
According to Scheme 4 Step 1 Method A: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (1.38 mmol, 500 mg) and N-chlorosuccinimide (1.38 mmol, 184 mg) in DMF (3 mL) was stirred for 1 hour at 50° C. The reaction mixture was diluted with AcOEt (250 mL) and the organic phase was washed with a saturated solution of Na2CO3. The organic phase was dried over MgSO4, was filtered and was concentrated to yield N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-chlorothiazol-2-yl)pyridin-2-amine (1.16 mmol, 460 mg, 84%) as a beige solid.
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([O:22]C)=[CH:14][CH:13]=1>ClCCl>[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:3]([O:2][CH3:1])=[C:14]([CH:15]=[O:22])[CH:13]=1
Reactant: COc1ccc(F)c2ccccc12
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C=O)cc(F)c2ccccc12
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
5.25 mL of dichloromethyl methyl ether were dissolved in 40 mL dichloromethane and cooled to +5° C. 6.75 mL tin(IV)chloride were added neat over 45 min to the solution. After the addition the mixture was stirred for 45 min at 5° C. 11.4 g 4-fluoro-1-methoxynaphthalene in 30 mL dichloromethane was added over 1 h. Then the cooling bath was removed, and the mixture was stirred for 2 h at ambient temperature. It was then poured into ice/water. The dichloromethane layer was separated and the aqueous phase was extracted with dichloromethane. The combined dichloromethane layers were washed with water, dried over sodium sulfate, filtered through celite and concentrated in vacuo. The residue was treated with pentane to yield 9.3 g of 4-fluoro-1-methoxynaphthalene-2-carbaldehyde as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]([C:24]2[CH:41]=[CH:40][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])=[CH:26][CH:25]=2)[CH2:21][CH2:22][CH3:23])[C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([CH3:18])[C:12]=2Cl)=O)=[CH:4][CH:3]=1.O.[NH2:43][NH2:44]>CS(C)=O.[Na+].[Cl-]>[Cl:17][C:15]1[CH:16]=[C:11]2[C:12](=[C:13]([CH3:18])[CH:14]=1)[NH:44][N:43]=[C:9]2[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:20]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])=[CH:40][CH:41]=1)[CH2:21][CH2:22][CH3:23]
Reactant: NN
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(Cl)cc(C)c1Cl)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1n[nH]c2c(C)cc(Cl)cc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a solution of the major diastereomer of the product of Step A (271 mg, 0.439 mmol) in DMSO (25 mL) was added hydrazine hydrate (60 wt %, 0.90 mL, 11 mmol). The mixture was stirred at 100° C. for two days in a sealed tube. The mixture was diluted with saturated NaCl (aq) then extracted twice with ethyl acetate. The combined organic layers were then washed with 2 N HCl (aq), saturated NaHCO3 (aq), and saturated NaCl (aq). The organic layer was dried over sodium sulfate, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford the major diastereomer of the title compound as a solid. This diastereomer was resolved to provide enantiopure material by supercritical fluid chromatography on a ChiralPak OJ-H column (2 cm×25 cm) eluting with 50 mL/min of 20% (MeOH+0.1% Et2NH) and 80% CO2 at 35° C. and 100 bar. LC1 2.58 min. (M-tBu+H)+ 538.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of p-fluorobenzamide (5 g), ethyl bromopyruvate (9.92 ml), and sodium hydrogen carbonate (15 g) in tetrahydrofuran (150 ml) was refluxed for 20 hours. After cooling the reaction mixture, insoluble material was removed by filtration through Cellite and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml) and trifluoroacetic anhydride (30 ml) was added to the mixture in an ice bath. After stirring at room temperature for one hour, a saturated aqueous sodium hydrogen carbonate solution was added to the mixture in an ice bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: ethyl acetate n-hexane=1:9) to obtain ethyl 2-(4-fluorophenyl)oxazol-4-carboxylate (7.44 g) as colorless solid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25]>C(O)C>[C:24]([NH:23][CH2:22][CH2:21][NH:20][C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])(=[O:26])[CH3:25]
Reactant: CC(=O)NCCN
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Solvent: CCO
Product: CC(=O)NCCNC(=O)c1nc(Cl)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 104 %

Procedure:
A mixture of 56 mg (0.2 mmol) of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester from example B-1 c), 227 mg (2 mmol) of N-(2-amino-ethyl)-acetamide and 0.8 ml of absolute ethanol was stirred at ambient temperature for 3 days. Then the solvent was evaporated in vacuo, the residue suspended in 3 ml of water, and the pH of the mixture was adjusted 2 to 3 by the addition of aqueous 1N HCl. The mixture was extracted with 2×25 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuo to give a yellowish solid. 64 mg of the title compound were obtained; MS-(+)-ion: M+1=308.1.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>C(O)C>[CH:1]([C@H:14]1[CH2:20][C@H:19]([OH:18])[C@@H:17]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Product: O[C@H]1C[C@H](C(c2ccccc2)c2ccccc2)OC[C@@H]1NCc1ccc(F)cc1

Procedure:
(1R,4R,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane, 28c, (0.02 g, 0.075 mmol) was reacted with para-fluoro-benzylamine (0.19 g, 1.50 mmol) in ethanol (Procedure E) to yield (2R,4S,5S)-2-benzhydryl-5-(4-fluoro-benzylamino)-tetrahydropyran-4-ol, (+)-29b, 0.028 g (94%, [α]D=(+)77.6, c=1, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][NH:17][C:18]([C:20]3[N:21]=[CH:22][C:23]([C:26]([OH:28])=O)=[N:24][CH:25]=3)=[O:19])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][NH:17][C:18]([C:20]3[CH:25]=[N:24][C:23]([C:26]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:28])=[CH:22][N:21]=3)=[O:19])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C1COCCN1
Reactant: N#Cc1ccc(-c2ccn(CCNC(=O)c3cnc(C(=O)O)cn3)n2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cnc(C(=O)N4CCOCC4)cn3)n2)cc1Cl
Reaction time: 8 h

Procedure:
5-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)ethylcarbamoyl)pyrazine-2-carboxylic acid (0.11 g; 0.29 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.083 g: 0.43 mmol), anhydrous HOBt (0.058 g; 0.43 mmol), dipea (0.075 ml; 0.43 mmol) and morpholine (0.025 g; 0.29 mmol) were dissolved in 5 ml of dry DCM and stirred overnight. The solution was diluted with 10 ml of DCM and washed with 3×5 ml water. The combined water phases were extracted with 2×5 ml DCM and the combined organic phases dried over Na2SO4, filtered and evaporated to dryness. The product was purified using flash chromatography DCM/MeOH as gradient eluent. Yield 0.06 g. 1H-NMR (400 MHz; d6-DMSO): δ 3.45 (t, 2H), 3.56 (t, 2H), 3.69 (s, 4H), 3.76-3.80 (m, 2H), 4.42 (t, 2H), 6.97 (d, 1H), 7.87 (d, 1H), 7.94-8.01 (m, 2H), 8.01 (s, 1H), 8.93 (d, 1H), 9.13 (s, HA), 9.22-9.25 (t, 1H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH:1]1([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.8 %

Procedure:
Cyclohexanone (59 mg), 5-aminoindazole (67 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (94 mg, yield 87%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([Cl:29])[C:27]=1[OH:28])[NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:22]=[C:21]([Cl:20])[C:27]([OH:28])=[C:26]([Cl:29])[CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Oc1c(Cl)cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1Cl

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,5-dichloro-4-hydroxyaniline were reacted to produce N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.50 (bs, 1H), 9.26 (bd, 2H, J=7.5 Hz), 8.06 (d, 1H, J=3.9 Hz), 7.65 (s, 2H), 7.18-7.13 (m, 2H), 6.80 (d, 1H, J=9.0 Hz), 4.20 (s, 4H); LCMS: purity: 100%; MS (m/e): 424 (MH+).
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[C:20]([C:26]([O:28][CH3:29])=[O:27])=[N:21][C:22](Br)=[CH:23][N:24]=1>COCCOC.O.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]>[NH2:18][C:19]1[C:20]([C:26]([O:28][CH3:29])=[O:27])=[N:21][C:22]([C:12]2[CH:13]=[CH:14][C:9]([S:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:8])=[O:7])=[CH:10][CH:11]=2)=[CH:23][N:24]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: O=S(=O)(c1ccc(B(O)O)cc1)N1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccc(S(=O)(=O)N3CCCC3)cc2)cnc1N
Temperature: 160 °C
Yield: 245.3 %

Procedure:
4-(Pyrrolidin-1-ylsulfonyl)phenylboronic acid (0.33 g, 1.29 mmol), methyl 3-amino-6-bromopyrazine-2-carboxylate (0.25 g, 1.08 mmol; described in: H. Ellingson, J. Amer. Chem. Soc. 1949, 2798), K3PO3 (3 M, 1.1 mL, 3.2 mmol), and Pd(dppf)Cl2 (0.044 g, 54 μmol) were suspended in ethylene glycol dimethyl ether/water (1.5:0.5 mL) and heated in a microwave oven at 160° C. for 10 min. The reaction was repeated 3 times. The combined product mixtures were evaporated with silica gel and the crude product was purified by chromatography on silica gel using a heptane to ethyl acetate gradient to give 0.96 g (82% yield) of the title compound: MS (ES) m/z 363 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]([CH3:29])[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([Cl:22])=[CH:17]3)=[O:12])OCC[O:3]1.O1CCOCC1.Cl>O>[O:3]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]([CH3:29])[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]2[C:21]=1[CH:20]=[CH:19][C:18]([Cl:22])=[CH:17]2)=[O:12]
Reactant: Cn1c(C(=O)NCCCC2(C)OCCO2)c2ccc(Cl)cc2c1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)CCCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C

Procedure:
A suspension of 8.3 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [3-(2-methyl-1,3-dioxolan-2-yl)propyl]amide in a mixture of 40 ml. of dioxane and 10 ml. of water is treated with 2 ml. of concentrated hydrochloric acid and then boiled at reflux for 3 hours. The solution obtained is concentrated to dryness under reduced pressure and the residue triturated with diethyl ether, and there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (4-oxopentyl)amide having a melting point of 128°-131° C. which can be used in the process without further purification. An analytical sample is obtained by recrystallization from ethanol and has a melting point of 136°-138° C.