Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([CH:25]2[C:34]3[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=3)[CH2:28][CH2:27][C:26]2=O)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:28]2[C:29]3[C:34](=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:25]([C:23](=[O:24])[C:22]3[CH:38]=[CH:39][C:19]([O:18][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:20][CH:21]=3)=[CH:26][CH2:27]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CCC(=O)C2C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2CC=C(C(=O)c3ccc(OCc4ccccc4)cc3)c3ccc(OC)cc32)cc1
Temperature: 45 °C

Procedure:
To a solution of about 50 grams (0.24 mole) of p-methoxyphenylmagnesium bromide in tetrahydrofuran (THF) were added at room temperature 30.2 grams (0.08 mole) of 1-(p-benzyloxybenzoyl)-6-methoxy-2-tetralone dissolved in THF. Upon completion of the addition, the entire mixture was warmed to 45° C. Analysis of a sample of the mixture by thin-layer chromatography (TLC) showed the absence of starting material. The mixture then was poured into aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extract was washed, dried, and evaporated. The resulting residue was dissolved in benzene, and a catalytic amount of p-toluenesulfonic acid was added. The mixture was stirred at room temperature until a TLC of the mixture indicated the absence of any carbinol intermediate. The mixture then was washed with water, dried, and concentrated. The residue was chromatographed over one kg. of alumina using 6 l. of benzene. The product was eluted with a mixture of 2 percent ethyl acetate in benzene. The product, 3-(4-methoxyphenyl-4-(4-benzyloxybenzoyl)-7-methoxy-1,2-dihydronaphthalene was obtained as an oil.
Reaction SMILES: [BH4-].[Na+].[N:3]([CH2:6][C:7]1[CH:14]=[C:13]([F:15])[C:10]([C:11]#[N:12])=[C:9]([F:16])[CH:8]=1)=[N+]=[N-].Cl>O.[Pd]>[NH2:3][CH2:6][C:7]1[CH:8]=[C:9]([F:16])[C:10]([C:11]#[N:12])=[C:13]([F:15])[CH:14]=1
Reactant: N#Cc1c(F)cc(CN=[N+]=[N-])cc1F
Agent: [Pd]
Agent: Cl
Agent: [BH4-]
Solvent: O
Product: N#Cc1c(F)cc(CN)cc1F

Procedure:
This reaction was carried out according to the procedure described in J. Chem. Res. (M) (1992) 3128. To a suspension of 520 mg of 10% Pd/C (50% moisture) in 20 mL of water was added a solution of sodium borohydride (0.834 g, 0.0221 mol) in 20 mL of water. Some gas evolution resulted. 4-Azidomethyl-2,6-difluorobenzonitrile (1.26 g, 6.49 mmol; see step (v) above) was dissolved in 50 mL of TH-F and added to the aqueous mixture on an ice bath over 15 min. The mixture was stirred for 4 h, whereafter 20 mL of 2M HCl was added and the mixture was filtered through Celite. The Celite was rinsed with more water and the combined aqueous phase was washed with EtOAc and subsequently made alkaline with 2M NaOH. Extraction three times with methylene chloride followed and the combined organic phase was washed with water, dried (Na2SO4) and evaporated. Yield: 0.87 g (80%).
Reaction SMILES: [Si]([N:8]1[C:11](=[O:12])[C@H:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:15]=2)[C@H:9]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])(C(C)(C)C)(C)C.[F-].[NH4+].C(O)(=O)C>CO.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:24]([O:23][C:21]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]1[CH:15]=[C:14]([CH2:13][C@H:10]2[C:11](=[O:12])[NH:8][C@@H:9]2[C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH:19]=[CH:18][N:17]=1)=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(C[C@H]2C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]2C(=O)OCc2ccccc2)ccn1
Agent: O=C([O-])O
Agent: [F-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(C[C@H]2C(=O)N[C@@H]2C(=O)OCc2ccccc2)ccn1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Ester 18 (127 mg, 0.20 mmol) was dissolved in 1 mL dry methanol at room temperature. 1 mL of a 0.5 M solution of ammonium fluoride in methanol (0.5 mmol, 2.5 equiv.) was added, then 60 mg acetic acid (1 mmol, 5 equiv). The reaction was stirred overnight under argon, diluted with 20 mL ethyl acetate and 20 mL saturated sodium bicarbonate solution. The water layer was washed with 3 portions of ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with 3:1 methylene chloride/ethyl acetate to yield 19 (72 mg, 69%). MS: 611.2 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:16])[C:6]1[CH:11]=[C:10]([C:12]#[CH:13])[CH:9]=[C:8]([C:14]#[CH:15])[CH:7]=1)([CH3:3])[CH3:2].[C:17]([O:20][CH2:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[F:32])(=[O:19])[CH3:18].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[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>[CH:1]([O:4][C:5](=[O:16])[C:6]1[CH:11]=[C:10]([C:12]#[CH:13])[CH:9]=[C:8]([C:14]#[C:15][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])=[O:33])=[C:26]([F:32])[CH:27]=2)[CH:7]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1cc(C#C)cc(C(=O)OC(C)C)c1
Reactant: CC(=O)OCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#Cc1cc(C#Cc2ccc(CC(=O)OCOC(C)=O)c(F)c2)cc(C(=O)OC(C)C)c1

Procedure:
Following General Procedure B and using 3,5-diethynyl-benzoic acid isopropyl ester (Intermediate 2.06, 0.27 g, 1–0.27 mmol), (2-fluoro-4-iodo phenyl)-acetic acid acetoxymethyl ester (0.224 g, 0.64 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 2.5–20% ethyl acetate in hexane as the eluent, the title compound was obtained as an orange solid (0.09 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][NH:13][CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:13]([C:25](=[O:26])[C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=4)[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccc(Cl)cc21
Reactant: O=C(Cl)c1cccc(F)c1
Product: CCOC(=O)C1=CN(C(=O)c2cccc(F)c2)CCc2c1[nH]c1ccc(Cl)cc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 9-chloro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 3-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.61 (1H, br s), 8.07 (1H, s), 7.46 (2H, m), 7.28 (4H, m), 7.14 (1H, dd), 4.25 (2H, q), 4.19 (2H, t), 3.21 (2H, t), 1.22 (3H, t); MS (ES): 413 (MH+).
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[N:10]1([C:19]2[CH:50]=[CH:49][C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][S:30][CH2:31][C@H:32]([NH:36][C:37](=[O:48])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([N+:45]([O-:47])=[O:46])[CH:40]=4)[C:33]([OH:35])=[O:34])=[CH:25][CH:24]=3)=[CH:21][CH:20]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>C(O)(=O)C.C(OCC)(=O)C>[N:10]1([C:19]2[CH:20]=[CH:21][C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][S:30]([CH2:31][C@H:32]([NH:36][C:37](=[O:48])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([N+:45]([O-:47])=[O:46])[CH:40]=4)[C:33]([OH:35])=[O:34])=[O:5])=[CH:25][CH:24]=3)=[CH:49][CH:50]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)N[C@@H](CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N[C@@H](CS(=O)Cc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
Sodium perborate tetrahydrate (97 mg, 0.63 mmol) was added as a solid to a stirred solution of (2R)-3-(4′-Indol-1-ylbiphen-4-ylmethylsulfanyl)-2-[2-(3-nitrophenyl)-acetylamino]-propionic acid (330 mg, 0.58 mmol) in acetic acid (10 mL) at 40° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by trituration of the product with diethyl ether afforded the title compound as a light brown solid (206 mg, 61%): mp. 197-198° C. Rf 0.15 (15% methanol in dichloromethane): 1H NMR (DMSO-d6, 300 MHz) δ 8.46 (1H, d, J=8 Hz, NH), 8.18 (1H, t, J=2 Hz, Ar—H), 8.08 (1H, ddd, J=8, 2, 1 Hz, Ar—H), 7.87 (2H, d, J=8 Hz, Ar—H), 7.72 (2H, d, J=8 Hz, Ar—H), 7.54-7.69 (7H, m, Ar—H), 7.35 (2H, d, J=8 Hz, Ar—H), 7.21 (1H, td, J=7, 2 Hz, Ar—H), 7.14 (1H, td, J=7, 2 Hz, Ar—H), 6.71 (1H, d, J=3 Hz, Ar—H), 4.36 (1H, m, CHN), 4.20 (1H, d, J=13 Hz, PhCHHS), 3.84 (1H, d, J=13 Hz, PhCHHS), 3.66 (2H, m, PhCH2CO), 3.11 (1H, dd, J=13, 5 Hz, CHHCHN), 2.99 (1H, dd, J=13, 8 Hz, CHHCHN); ESI-LCMS e/z calcd for C32H27N3O6S 581.646, found 582 (M+H)+, 604 (M+Na)+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]2[N:37]([CH3:38])[CH2:36][CH2:35][N:34]([CH3:39])[C:33]2=[O:40])[CH:29]=[CH:30][CH:31]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]5[C:33](=[O:40])[N:34]([CH3:39])[CH2:35][CH2:36][N:37]5[CH3:38])[CH:27]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CN1CCN(C)C(c2cccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)c2)C1=O

Procedure:
N-tert-Butyl-3-{2-[3-(1,4-dimethyl-3-oxo-piperazin-2-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzenesulfonamide was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1061. Product isolated as a yellow foam (74 mg, 44%). LCMS (m/e) 548 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.74 (s, 1H), 8.58 (s, 1H), 8.44 (d, 1H, J=7.9 Hz), 7.86 (d, 1H, J=7.8 Hz), 7.80 (d, 1H, J=8.2 Hz), 7.65-7.55 (m, 1H), 7.44-7.35 (m, 2H), 7.09 (d, 1H, J=7.6 Hz), 7.05 (d, 1H, J=4.8 Hz), 6.89 (s, 1H), 6.85 (d, 1H, J=4.8 Hz), 4.71 (s, 1H), 3.77-3.64 (m, 1H), 3.69 (s, 1H), 3.26-2.97 (m, 1H), 2.99 (s, 3H), 2.73-2.62 (m, 1H), 2.17 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:39]([C:40]3[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:42][CH:41]=3)=[CH:38][C:37]([CH2:50][C:51]([OH:53])=O)=[C:36]2[CH3:54])=[CH:31][CH:30]=1.[N+]([O-])([O-])=O.[NH2:59][C@@H:60]([CH2:64][O:65][N+:66]([O-:68])=[O:67])[C:61]([OH:63])=[O:62].Cl>C1COCC1>[O:65]([CH2:64][C@H:60]([NH:59][C:51](=[O:53])[CH2:50][C:37]1[CH:38]=[C:39]([C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:47])=[O:48])=[CH:42][CH:41]=2)[N:35]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[C:36]=1[CH3:54])[C:61]([OH:63])=[O:62])[N+:66]([O-:68])=[O:67]
Reactant: Cc1c(CC(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: N[C@@H](CO[N+](=O)[O-])C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1c(CC(=O)N[C@@H](CO[N+](=O)[O-])C(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
TEA (0.5 ml) and BOP (0.84 mmol) are added to a solution of acid 6g (0.7 mmol) in THF. After 1 h, the nitrate of (S)-2-amino-3-nitroxypropionic acid (1.5 mmol) is added and it is stirred for a further 2 h at RT. Then it is concentrated and the residue is dissolved in 10% K2CO3, then it is filtered. The solution thus obtained is acidified to pH 2 with 2N HCl and the precipitate obtained is filtered and dried; yield 80%, m.p. 109° C. FT-IR cm−1: 3300 (ν N—H), 1734 (ν C—O), 1640 (ν C—O), 1520 (δ N—H), 1278 (ν C—N), 1595 (νasO—NO2), 865 (νsO—NO2). 1H NMR (400 MHz, CDCl3): δ 7.70 (d, 2H), 7.30 (m, 4H), 7.23 (m, 2H), 6.73 (s broad, 1H), 6.50 (s, 1H), 4.70 (m, 1H), 4.20 (m, 2H), 3.54 (s, 2H), 3.01 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]=[CH:5][C:4]2[CH:8]=[CH:9][S:10][C:3]1=2.CN(C=O)C.[H-].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1>[Cu](I)I.O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:1][C:2]2[C:3]3[S:10][CH:9]=[CH:8][C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: Clc1ccc(I)cc1
Reactant: O=C1CN=Cc2ccsc21
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Oc2cncc3ccsc23)cc1
Temperature: 25 °C

Procedure:
Example 145D can be processed as in Lindley (Tetrahedron, 1983, 1433). A solution of Example 145C (1.0 mmol) and DMF (2.0 mL) is treated at 0° C. with sodium hydride (1.0 mmol), slowly warmed to room temperature, treated with 1-chloro-4-iodobenzene (1.0 mmol) and copper iodide (0.1 mmol), heated at 80° C. overnight, and cooled. The solution is poured into water and extracted with diethyl ether. The extracts are combined, dried (MgSO4), filtered, and concentrated. Recrystallization from ethyl acetate/hexanes provides the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([Cl:14])[S:13][C:9]=2[CH:8]=1.Cl>C1(C)C=CC=CC=1>[Cl:14][C:12]1[S:13][C:9]2[CH:8]=[C:7]([OH:6])[CH:16]=[CH:15][C:10]=2[N:11]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Oc1ccc2nc(Cl)sc2c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
Aluminum chloride (1.98 g, 14.9 mmol) was added to a solution of 6-methoxy-2-chlorobenzothiazole (1.06 g, 5.31 mmol) in toluene (40 mL), and the reaction mixture was heated to 110° C. After 1 h, the reaction mixture was allowed to cool to rt and 1 M aqueous HCl (40 mL) was added. The resulting precipitate was collected by filtration and washed with water (2×), saturated aqueous NaHCO3 (2×) and water (2×). The solid was air-dried, yielding 0.800 g (81%) of the title compound as a brown solid. LC-MS: RT=7.18 min., [M+H]+=185.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36]>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][C:29]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[CH:30][CH:31]=3)(=[O:24])=[O:25])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CN(C)CCN
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccnc2)cc(OC)c1
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(NCCN(C)C)nc2)cc(OC)c1
Reaction time: 8 h
Yield: 19.1 %

Procedure:
N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (100 mg, 0.21 mmol), KHCO3 (40 mg, 0.40 mmol), N1,N1-dimethylethane-1,2-diamine (225 μl, 2.0 mmol) and dry DMF (1.0 mL) were combined and heated to 130 C. with stirring overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(2-(dimethylamino)ethylamino)pyridine-3-sulfonamide (21.0 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (br s, 1H), 8.63 (d, 1H), 8.07 (dd, 1H), 7.40 (m, 1H), 7.34 (m, 1H), 7.28 (d, 2H), 7.14 (m, 4H), 6.47 (d, 1H), 6.12 (m, 1H), 3.75 (s, 6H), 3.35 (m, 2H), 3.14 (m, 2H), 2.74 (s, 6H). MS (EI) for C25H29N7O4S: 524.1 (MH+).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1.[CH3:22]O>>[CH3:22][C:19]1[C:10]([CH2:9][O:8][C:7]2[CH:20]=[CH:21][C:4]([Br:3])=[CH:5][CH:6]=2)=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1ccccc1COc1ccc(Br)cc1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C(=O)O)c1COc1ccc(Br)cc1
Reaction time: 8 h
Yield: 84 %

Procedure:
A 2 mol/L aqueous sodium hydroxide solution (250 mL) was added to a methanol (1 L) solution of methyl 2-(4-bromophenoxymethyl)-benzoate (139 g, 432 mmol), and the mixture was stirred overnight while heating under reflux. Methanol was distilled off under a reduced pressure, and a 6 mol/L hydrochloric acid was added to the residue obtained to precipitate the crystals, and the precipitated crystals were collected by filtration, and sufficiently washed with water. The crystals were dried over phosphorus pentoxide at 50° C., to give 112 g (84%) of the captioned compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9](C(=O)C(F)(F)F)[CH:8]=[CH:7]2)[CH3:3].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:3][CH:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)[CH3:1]
Reactant: CC(C)c1ccc2c(ccn2C(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1ccc2[nH]ccc2c1
Yield: 88.8 %

Procedure:
The trifluoroacetyl indole (D16, 0.25 g, 0.99 mmol) was stirred with potassium carbonate (0.20 g, 1.5 mmol) in methanol (7.5 ml) at 550 C for 1.5 h. Solvent was evaporated and the residue was partitioned between water and dichloromethane. The organic extract was dried and evaporated to give the title compound (0.14 g, 86%). NMR (CDCl3) δ: 1.30 (6H, d, J=7), 3.00 (1H, m, J=7), 6.48 (1H, m), 7.01 (1H, m), 7.09 (1H, d, J=8), 7.20 (1H, d, J=8), 7.49 (1H, s), 7.71 (1H, broad).
Reaction SMILES: [OH:1][C:2]([CH3:41])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37](C)[N:38]=[C:12]23)[CH2:7][CH2:6]1.C([Sn](=O)CCCC)CCC.[N:52]([Si](C)(C)C)=[N+:53]=[N-:54].C1(C)C=CC=CC=1>C(OCC)(=O)C>[OH:1][C:2]([CH3:41])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:54][N:53]=[N:52][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.2 g), dibutyltin oxide (0.046 g), azidotrimethylsilane (1.3 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium fluoride solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.93 mL) was added and the mixture was stirred at 70° C. for 1 hr. Ethyl acetate and 1 N hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.033 g, 15%).
Reaction SMILES: CC([O:5][C:6]([CH:8]1[C:13]([CH3:15])([CH3:14])[S:12][CH2:11][CH2:10][N:9]1[S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C:24]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:23]=1[O:22]2)(=[O:18])=[O:17])=[O:7])(C)C>FC(F)(F)C(O)=O>[CH:20]1[C:19]([S:16]([N:9]2[CH2:10][CH2:11][S:12][C:13]([CH3:15])([CH3:14])[CH:8]2[C:6]([OH:7])=[O:5])(=[O:18])=[O:17])=[CH:27][CH:26]=[C:25]2[C:21]=1[O:22][C:23]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:24]=12
Reactant: CC(C)(C)OC(=O)C1N(S(=O)(=O)c2ccc3c4c(oc3c2)CCCCCC4)CCSC1(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)SCCN(S(=O)(=O)c2ccc3c4c(oc3c2)CCCCCC4)C1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
The ester from Example 8 (0.184 g, 0.38 mmol) was diluted with trifluoroacetic acid (5 mL) and stirred at room temperature for overnight. The solution was poured over ice, and the resulting solid was collected by filtration and dried in vacuo to give the acid (0.133 g, 80%) as a cream colored solid. 1HNMR (DMSO-d6) δ 12.7 (bs, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 4.3 (s, 1H), 3.9 (m, 1H), 3.6 (m, 1H), 2.9 (m, 3H), 2.8 (m, 2H), 2.3 (m, 1H), 1.8 (m, 2H), 1.7 (m, 2H), 1.5 (m, 2H), 1.49 (s, 3H), 1.2 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[NH:8][C:7]=1[NH2:27])=[O:5])[CH3:2].[CH3:28][CH2:29][O-].[Na+].C(Br)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:28][CH3:29])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:26])[N:8]=[C:7]1[NH2:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCBr
Product: CCOC(=O)C1=C(C)N=C(N)C(CC)(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A solution of 37.4 g of 2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol is brought to the boil and treated with 10.9 g of ethyl bromide. After boiling for a further 60 minutes under reflux, the mixture is concentrated by distillation and the residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water. Concentration of the organic phase and recrystallization from ethanol gave 2-amino-3-ethyl-6-methyl-4-(3'-nitrophenyl)-3,4 -dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 122°-3° C (16.5 g, 41% of theory).
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)#[N:2]>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][C:4]1[N:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2ccc(CC#N)nc2)cc1
Agent: [Ni]
Solvent: CCO
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(CCN)nc2)cc1

Procedure:
A mixture of N-(6-cyanomethyl-pyridin-3-yl)-4-isopropyl-benzenesulfonamide (1.7 g, 5.4 mmol) aqueous ammonia (45 ml) and raney-nickel (2.7 mmol) in ethanol (50 ml) was hydrogenated at atmospheric pressure. After filtration the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 and the aqueous layer extracted five times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and the solvent evaporated under reduced pressure to give the product as a yellow powder after recrystallisation from methanol/ethyl acetate (1.3 g, 73%).