Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2>COCCO>[NH:36]1[C:37]2[C:33](=[CH:32][C:31]([NH:30][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[O:19][CH3:20])[N:6]4[N:5]=3)=[CH:39][CH:38]=2)[CH:34]=[CH:35]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4[nH]ccc4c3)nn12
Yield: 23.1 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 5-Aminoindole (115 mg, 0.000870 mol) were dissolved in 2-Methoxyethanol (3.05 mL) and the The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 35.70 mg of (1H-Indol-5-yl)-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a lyophilized powder. (M+H)=356.18. 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.41 (s, 1H), 8.17 (m, 2H), 8.05 (d, 1H, J=6.13 Hz), 7.54 (m, 1H), 7.29 (m, 4H), 7.22 (m, 3H), 6.41 (m, 1H), 3.85 (s, 3H).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Cl:11][C:12]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][NH:19][OH:20])=[O:15]>N1C=CC=CC=1>[Cl:11][C:12]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:13]=1[C:14]([NH:16][CH2:17][CH2:18][N:19]([CH:8]=[O:10])[OH:20])=[O:15]
Reactant: O=C(NCCNO)c1cccc(Cl)c1Cl
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=CN(O)CCNC(=O)c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 15 %

Procedure:
A mixture of acetic anhydride (5 mL) and formic acid (2.5 mL) was allowed to stand at 55° C. for 2.5 h. After cooling to 0° C., the resulting mixed anhydride was added to a solution of 2,3-dichloro-N-(2-hydroxyamino-ethyl)-benzamide (10.5 g, 42 mmol) in pyridine (50 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred for 2 h and the pyridine was removed in vacuo. The residue was chased three times with water and three times with MeOH. The residue was partitioned between cold brine/1N HCl and dichloromethane/MeOH (9:1). The aqueous layer was extracted (10×100 mL) with dichloromethane/MeOH (9:1). The combined organic extracts were dried (Na2SO4) and were concentrated. Purification by preparative reverse-phase HPLC provided the title compound (1.8 g, 15%) as a white solid. 1H NMR* (400 MHz, CD3OD): δ 8.35 (s, 0.5H); 7.95 (s, 0.5H); 7.60 (m, 1H); 7.35 (m, 2H); 3.79 (m, 1H); 3.73 (m, 1H); 3.62 (m, 2H). * 1:1 mixture of rotamers. ESMS: M+H=277.
Reaction SMILES: [C:1]1([NH:11][C:12]2[CH:13]=[C:14]([C:20]3[N:25]=[C:24](CNC(=O)OC(C)(C)C)[CH:23]=[N:22][CH:21]=3)[CH:15]=[N:16][C:17]=2[O:18]C)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.[NH+:36]1C=CC=C[CH:37]=1>C([O-])([O-])=O.[Na+].[Na+]>[C:1]1([NH:11][C:12]2[C:17](=[O:18])[NH:16][CH:15]=[C:14]([C:20]3[CH:21]=[N:22][CH:23]=[C:24]([NH:36][CH3:37])[N:25]=3)[CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: c1cc[nH+]cc1
Reactant: COc1ncc(-c2cncc(CNC(=O)OC(C)(C)C)n2)cc1Nc1nccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CNc1cncc(-c2c[nH]c(=O)c(Nc3nccc4ccccc34)c2)n1
Yield: 27 %

Procedure:
tert-butyl 6-(5-(isoquinolin-1-ylamino)-6-methoxypyridin-3-yl)pyrazin-2-ylmethylcarbamate (75 mg, 0.16 mmol, 1 eq.) and pyridinium hydrochloride (378 mg, 3.27 mmol, 20 eq.) were stirred at 150° C. for 10 minutes, allowed to cool to Rt and diluted with sat. Na2CO3 (10 mL). The resulting suspension was sonicated and filtered. The solid collected was washed with water (3×10mL), iso-propanol (1×5mL), diethyl ether (3×10 mL) and pentane (3×10 mL) to give a light brown powder (14.9 mg, 27% Yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:11][NH2:12]>C(O)C.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:12][CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNc1cccc(F)c1C#N
Temperature: 80 °C
Yield: 99.6 %

Procedure:
To a stirred solution of 2,6-difluorobenzonitrile (3.5 g, 25.2 mmol) in ethanol (40 mL) was added 2 mL of methylamine (40 wt %, in H2O) and heated at 80° C. for 2 h. The mixture was then diluted with water and the resulting slurry extracted with dichloromethane (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the title product as a white solid (3.77 g, 99.6% yield). 1HNMR (500 MHz, CDCl3) δ: 7.35–7.31 (1H, m), 6.41–6.38 (2H, m), 4.74 (1H, br s), 2.93 (3H, d, J=5.19 Hz). LCMS calcd for C8H8FN2 (M+H): 151.07.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[N:19]=[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[N:19]=[C:12]3[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[C:16]([Br:20])[N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2nc3c(OC)cccn3n2)CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C1(c2nc3c(OC)ccc(Br)n3n2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
To a stirred solution of 1-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridine-2-yl)-cyclopropanecarboxylic acid ethyl ester (25 g, 95.7 mmol) in acetonitrile (300 mL) at RT, N-bromosuccinimide (34 g, 191.5 mmol) was added portion wise. After addition the reaction mixture was stirred at RT for 6 hours. The reaction mixture was diluted with EtOAc (600 mL), washed with water (100 mL×2), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel column chromatography (0 to 10% EtOAc in dichloromethane as eluent) to afford the title compound (25 g, 77%, colorless solid). 1H NMR (400 MHz, DMSO): δ=7.44 (d, J=8.4 Hz; 1H), 7.07 (d, J=8 Hz; 1H), 4.13-4.08 (m, 2H), 3.97 (s, 3H), 1.60-1.57 (m, 2H), 1.48-1.45 (m, 2H), 1.13 (t, J=7.4 Hz; 3H) ppm.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH:21]1[CH:26]=[N:25][CH:24]=[C:23]([N:27]=[C:28]=[O:29])[CH:22]=1>ClCCl>[N:25]1[CH:26]=[CH:21][CH:22]=[C:23]([NH:27][C:28]([N:2]2[CH2:3][CH:4]([O:6][C:7]3[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=3)[CH2:5]2)=[O:29])[CH:24]=1
Reactant: O=C=Nc1cccnc1
Reactant: Ic1ccc(OC2CNC2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)N1CC(Oc2ccc(I)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
2-(Azetidin-3-yloxy)-5-iodo-pyridine hydrochloride (4.2 g, 13 mmol) was suspended in anhydrous dichloromethane (50 mL) and triethylamine (5.5 mL) was added. Pyridine-3-isocyanate (1.45 g, 11.7 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 hr. The suspension solvents were removed in vacuo and the residue partitioned between ethyl acetate (400 mL) and sat. aqueous sodium bicarbonate solution (400 mL). The mixture was filtered through a pad of celite and the filtrate phases were separated. The organic phase was washed with sat. aqueous sodium bicarbonate solution (250 mL), then sat aqueous sodium chloride solution (250 mL) and dried over sodium sulphate and filtered. The filtrate solvents were removed in vacuo to afford a yellow solid which was purified by flash chromatography on silica gel (100 g), eluting with a 1:19 mix of 7N ammonia in methanol solution: dichloromethane. This affords the title compound (2.0 g, 42%) as a colourless solid.
Reaction SMILES: [H-].[Na+].Cl.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[CH3:16].I[CH2:25][CH3:26]>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:25][CH3:26])[CH:18]=1)[CH3:16]
Reactant: CCI
Reactant: C[C@@H](NCCCc1ccccc1Cl)c1cccc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOc1cccc([C@@H](C)NCCCc2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NPS R-568 (30.3 g 100 mmol) in dichloromethane at −78° C. was treated dropwise with borontribromide (50 g, 200 mmol). The reaction 40 was stirred 1 hr at rt and poured over ice. The hydrobromide was extracted from the aqueous phase with chloroform. The chloroform solubles were then washed (4×100 ml) with 50% HCl. The chloroform wash was dried over anhydrous magnesium sulfate and concentrated to afford (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-hydroxyphenyl)ethylamine hydrochloride as a solid. A solution of sodium hydride (0.48 g, 20 mmol) in dimethylformamide was treated with (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-hydroxyphenyl)ethylamine hydrochloride (3.25 g, 10 mmol) and the reaction stirred 1 hr at rt. The reaction was treated with iodoethane (1.71 g, 11 mmol) and stirred 16 hr at rt. Work-up and chromatography through silica using 3% methanol in chloroform afforded (R)-N-[3-(2-chlorophenyl)propyl]-1-(3-ethoxyphenyl)ethylamine, 6T, as an oil; m/z (rel. int.) 316 (M+, 1), 302 (100), 282 (11), 196 (5), 178 (7), 149 (74), 121 (34), 103 (25), 91 (28), 77 (29).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[C:5]2=[O:22].[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:24]>C(#N)C>[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][N:29]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:22])[C:6]([C:19]([OH:21])=[O:20])=[CH:7][N:8]3[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:3][C:2]=2[F:1])[CH2:28]1)[CH3:24]
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1cn(CC(F)(F)F)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC(F)(F)F)c3c2F)C1
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To 0.76 g (2.33 mmol) of 6,7,8-trifluoro-1-(2,2,2-trifluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 7.0 ml of acetonitrile was added 0.355 g (2.33 mmol) of 1,8-diazobicyclo [5.4.0]undec-7-ene in 5 ml of acetonitrile followed by 0.29 g (2.33 mmol) of 3-[(ethylamino)methyl]-pyrrolidine. The mixture was refluxed for one hour and kept at room temperature overnight. The solids were collected and washed with ether to give 0.77 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-1-(2,2,2-trifluoroethyl)-3-quinolinecarboxylic acid, mp 222°-224° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C)C=O>[Cl:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: C1CNCCN1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1c(Cl)c(N2CCNCC2)cnn1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
55.1 g (200 mmol) of 2-(4-chlorophenyl)-4,5-dichlorpyridazin-3-one are introduced with 41.6 ml (300 mmol) of triethylamine in 400 ml of dimethylformamide. 137.82 g (1600 mmol) of piperazine are added, and the mixture is stirred at 80° C. overnight. The reaction mixture is cooled and then concentrated under high vacuum. The residue is taken up in dichloromethane and washed twice with water, dried over magnesium sulfate and concentrated. The product is isolated by chromatography (gradient: dichloromethane/methanol from 95:5 to 9:1) on silica gel and subsequent crystallization with ether.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][O:9][CH:10]2[C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[C:5]([CH3:18])[CH:4]=1.[BrH:19]>>[BrH:19].[NH:17]1[CH2:16][CH2:15][N:14]=[C:13]1[CH:10]1[C:11]2[C:6](=[C:5]([CH3:18])[CH:4]=[C:3]([OH:2])[CH:12]=2)[CH2:7][CH2:8][O:9]1
Reactant: COc1cc(C)c2c(c1)C(C1=NCCN1)OCC2
Agent: Br
Product: Cc1cc(O)cc2c1CCOC2C1=NCCN1
Temperature: 25 °C

Procedure:
2-(7-Methoxy-5-methylisochroman-1-yl)-4,5-dihydro-1H-imidazole (example 61, 100 mg) was dissolved in hydrobromic acid (1.5 mL, 47 w-% in water) and mixture was heated to reflux. After 5.5 hours mixture was cooled down to room temperature. Solvents were evaporated and the evaporation residue was triturated with ethanol to afford the title compound. (Yield 27 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N+:3]=1[O-].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14].C([O-])(O)=O.[Na+]>C(O)C>[C:13]([O:16][CH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1)(=[O:15])[CH3:14]
Reactant: Cc1cc(C(F)(F)F)cc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)OCc1cc(C(F)(F)F)ccn1
Reaction time: 0.17 h

Procedure:
2-Methyl-4-(trifluoromethyl)pyridine 1-oxide (4.0 g, 22 mmol) was added to acetic anhydride (12 mL) at 120° C. The mixture was refluxed for 1 h. To it was carefully added 10 mL of ethanol. Reflux was continued for 10 min. The mixture was poured into ice, neutralized with NaHCO3, and extracted with Et2O. The organic layer was dried (MgSO4) and concentrated. Chromatography on silica gel (5:2 hexanes/EtOAc) provided the product (3.4 g) as a brown oil. MS (M+H) 220.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:27]([CH3:28])=[C:26]([CH:29]=O)[NH:25][C:24]=2[CH3:31])=[O:22])[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:27]([CH3:28])=[C:26]([CH:29]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:25][C:24]=2[CH3:31])=[O:22])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCn1ccnc1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCCCn1ccnc1
Yield: 58.6 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.09 g, 0.4 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-imidazol-1-ylpropyl)amide (0.1 g) to give 0.1 g (59%) of the title compound as an orange solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[CH:7][CH:8]=1.Cl[S:13]([N:16]=C=O)(=[O:15])=[O:14].C1(C)C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][S:13](=[O:15])(=[O:14])[NH2:16])=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1ccc(C(F)(F)F)cc1
Yield: 78.7 %

Procedure:
This compound was prepared according to the procedure used in Example 56. A mixture of 9.6 g (0.059 mole) of α,α,α-trifluoro-p-cresol, 5.7 ml (9.2 g, 0.065 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 11.2 g (70%) of white solid, mp 111°-112° C. (benzene).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[CH:21][C:20]=2[CH3:26])=[C:15]([C:27]#[CH:28])[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].I[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[N:38]=[CH:37][CH:36]=[CH:35]2.C(N(CC)CC)C>CN1C(=O)CCC1.[Cu]I.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>[C:1]([O:5][C:6](=[O:30])[N:7]([CH:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([CH3:26])=[CH:21][N:22]=[CH:23][C:24]=2[CH3:25])=[C:15]([C:27]#[C:28][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]=[CH:37][CH:36]=[CH:35]3)[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Ic1ccc2ncccc2c1
Reactant: C#Cc1nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)ccc1-c1c(C)cncc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cncc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2ncccc2c1

Procedure:
A mixture of tert-butyl-N-[1-[[5-(3,5-dimethylpyridin-4-yl)-6-ethynylpyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate (E1a desilylated according to the general method exemplified for F1a) (50 mg, 0.12 mmol), 6-iodoquinoline (89 mg, 0.35 mmol), copper(I) iodide (2.2 mg, 0.01 mmol), Dichlorobis(triphenylphosphine)palladium(II) (8.1 mg, 0.01 mmol) and triethylamine (64 μl, 0.47 mmol) is stirred under argon atmosphere in NMP (0.5 ml) for 1 h at 50° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 28 mg (45%). HPLC-MS: M+H=536; tR=1.79 min (*Method—3).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12](OCC)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[CH2:12][OH:13])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccc(CCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc(CCc2ccccc2)c1
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Ethyl 3-phenethylbenzoate (180 mg) was dissolved in 2 ml of anhydrous tetrahydrofuran, and under ice cooling, 42 mg of lithium aluminum hydride was added by portions over 5 minutes. The mixture was stirred for one hour under ice cooling. Water (10 ml) was added to the reaction mixture to decompose the excess of the reducing agent. The mixture was then extracted with 20 ml of ethyl ether. The extract was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 140 mg (yield 93%) of 3-phenethylbenzyl alcohol.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([NH:28][C@@H:29]2[C:35](=[O:36])[N:34]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:33]3[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=3[S:31][CH2:30]2)[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C.C(OCC)C>C(O)(=O)C>[C:23]([C@H:22]([NH:28][C@@H:29]1[C:35](=[O:36])[N:34]([CH2:37][C:38]([OH:40])=[O:39])[C:33]2[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=2[S:31][CH2:30]1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:25])=[O:24]
Reactant: CCOC(=O)[C@@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@H](CCCCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 1 h
Yield: 67.7 %

Procedure:
In 1 ml of acetic acid is dissolved 0.5 g of tert-butyl 3(R)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1 hour. Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is dissolved in 20 ml of 1N aqueous sodium hydroxide solution, followed by allowing the solution to stand at room temperature for 30 minutes. The solution is neutralized by adding 2 ml of acetic acid, and purified by MCI-gel column chromatography (water:methanol=1:2). The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.23 g of 3(R)-[1(R)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[C:27]1[O:31][C:30]([CH3:32])=[N:29][C:28]=1[C:33](O)=[O:34]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:21]3[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=3[CH3:19])=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1ccc(C)c(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cc(C)ccc3C)cn2)o1

Procedure:
Following general procedure B followed by either C or D, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(2,5-dimethyl-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.01 min; [M+H]+=419.00.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].S(=O)(=O)(O)[OH:17]>O>[CH3:15][C:7]1[C:6]([OH:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(O)cccc1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Alternatively, the desired subtitled compound was prepared by adding 22.6 g (0.33 mol) of sodium nitrite in small portions to a cooled (-10° C.) solution of 45 g (0.30 mol) of 3-amino-2-methylbenzoic acid and 106 g (58 mL; 1.08 mol) of concentrated sulfuric acid in 400 mL of water, while maintaining the temperature below 7° C. The resultant reaction mixture was stirred for approximately 30 minutes at -10° C., poured into a solution of 240 mL of concentrated sulfuric acid in 1.2 L water, and then slowly heated to 80° C. (heavy gas evolution occurs between the temperatures of 40°-60° C.). When the gas evolution stopped, the reaction mixture was cooled to room temperature and the subtitled compound was extracted five times with ethyl acetate (600 mL). The combined organic phases were combined with 500 mL of an aqueous saturated sodium carbonate solution. The resultant layers were separated and the aqueous layer was acidified to pH 2 with concentrated hydrochloric acid. The titled compound was then extracted using ethyl acetate (500 mL) and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a crude material. This material was purified using two recrystallizations from an ethyl acetate/chloroform mixture to provide 23.2 g of a light orange powder. Yield: 52%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([CH3:21])=[CH:23][CH:24]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Yield: 83 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 4-methylbenzoyl chloride (1.1 g, 8.0 mmol) in THF (40 mL) was heated to reflux for 36 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with methanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-methyl-benzamide as a yellow solid (1.3 g, 83% yield): mp, 322–324° C.; 1H NMR (DMSO-d6) δ 2.06–2.10 (m, 1H, CHH), 2.41 (s, 3H, CH3), 2.50–2.65 (m, 2H, CH2), 2.83–2.97 (m, 1H, CHH), 5.19 (dd, J=5.3, 12.6 Hz, 1H, NCH), 7.42 (d, J=8.1 Hz, 2H, Ar), 7.67 (d, J=7.2 Hz, 1H, Ar), 7.86–7.93 (m, 3H, Ar), 8.62 (d, J=8.4 Hz, 1H, Ar), 10.37 (s, 1H, NH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.07, 21.99, 30.93, 48.99, 117.57, 118.58, 125.94, 127.28, 129.58, 130.44, 131.33, 136.34, 136.77, 142.96, 164.80, 166.65, 168.29, 169.69, 172.72; Anal Calcd for C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.65; H, 4.17; N, 10.70.