Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:12]=[C:11]([F:20])[C:10]=1[C:21]1[S:25][C:24]([N:26]2[CH2:29][C:28]3([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:27]2)=[N:23][N:22]=1)C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[F:20][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:14]=[C:9]([OH:8])[C:10]=1[C:21]1[S:25][C:24]([N:26]2[CH2:27][C:28]3([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:29]2)=[N:23][N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3c(F)cc(-c4cn[nH]c4)cc3OCc3ccccc3)s1)C2
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3c(O)cc(-c4cn[nH]c4)cc3F)s1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
A solution of tert-butyl 2-(5-(2-(benzyloxy)-6-fluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (86 mg, 0.149 mmol) in a 1:1: mixture MeOH:DCM (3 mL) was added to a nitrogen flushed flask containing 10% Pd/C (8.6 mg). The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 18 hours. The reaction mixture was flushed with nitrogen and an additional 8.6 mg of 10% Pd/C was added. The reaction was diluted with 1:1 MeOH:DCM (3 mL), and again placed under a hydrogen atmosphere (balloon) and stirred at room temperature for an additional 5 days. The reaction mixture was flushed with nitrogen, diluted with 10% MeOH in DCM (50 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford a pale brown/off-white solid. The solid was re-dissolved in 25% MeOH in DCM (10 mL) and added to a nitrogen flushed flash containing 10% Pd/C (8.6 mg). The reaction mixture was placed under a hydrogen atmosphere (balloon) and left to stir at room temperature for 18 hours. The reaction mixture was diluted with 10% MeOH in DCM (50 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford the crude product as a brown solid. The crude material was purified by flash chromatography using a 10 g silica cartridge running a MeOH/DCM gradient and collecting by mass to afford an the title compound as a pale brown solid (54 mg, 74% yield). LC-MS: Rt 1.33 min; MS m/z 487.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 11.92 (s, 1H), 8.36 (d, J=1.7 Hz, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.22 (dd, J=12.6, 1.6 Hz, 1H), 7.14-7.19 (m, 1H), 3.92 (s, 4H), 3.28-3.31 (m, 4H), 1.69-1.79 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](I)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:12][CH3:13])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(F)ccc1[N+](=O)[O-]

Procedure:
5-fluoro-2-nitrophenol (300 mg), ethyliodide (0.50 mL) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL), and reacted at 50° C. overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18](O)=[O:19])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([C:26]1([NH2:35])[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18](=[O:19])[NH:35][C:26]2([C:24]([O:23][CH2:21][CH3:22])=[O:25])[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCN(C(=O)OC(C)(C)C)C3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of 3,4-dihydro-1H-isoquinoline-2,5-dicarboxylic acid 2-tert-butyl ester (2 g, 7.2 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (1.5 g, 7.2 mmol), HATU (3.27 g, 8.6 mmol) in anhydrous DMF (20 mL) is added DIPEA (1.42 mL, 8.6 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (150 mL) and washed with water (1×20 mL) and brine (2×20 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (71) as white solid (1.02 g, 30%).
Reaction SMILES: [C:1]1([N:7]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:8]([O:10][CH2:11][CH2:12][C:13]2[C:22]3[C:17](=[C:18]([O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH:14]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].OO.C(OCC)(=[O:53])C>O1CCCC1.O>[C:41]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH2:11][CH2:12][C@@H:13]2[C:22]3[C:17](=[C:18]([O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@H:14]2[OH:53])=[O:9])[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC=C2CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](Oc1cccc2c1CC[C@@H](O)[C@@H]2CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 1-[2-(N,N-diphenylcarbamoyloxy)-ethyl]-5-t-butyldiphenylsilyloxy-3,4-dihydronaphthalene (2.0 g) in THF (tetrahydrofuran) (20 ml) was added BH3 (4.8 ml, 1M solution in THF) at 0° C. under N2. After being stirred for 12 hours at the room temperature, 2N-NaOH solution (1.5 ml) and H2O2 (1.0 ml, 35% solution) were added to the solution and stirred for 4 hours. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (trans)-1-[2-(N,N-diphenylcarbamoyl-oxy)ethyl]-2-hydroxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.1 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:35][S:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.O>CN(C)C=O.O>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[S:36][CH3:35])=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: CSc1ccccc1B(O)O
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccccc3SC)cc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (61 mg, 0.075 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 11) (354 mg, 0.75 mmol), sodium carbonate (239 mg, 2.25 mmol) and [2-(methylthio)phenyl]boronic acid (252 mg, 1.5 mmol) in N,N-dimethylformamide/water (2:1) (22.5 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylthio)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: C(N)(=N)[C:2]1C=C[N:5]=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([NH2:18])=[NH:17]>>[NH2:5][C:4]1[CH:3]=[CH:2][N:18]=[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[N:17]=1
Reactant: N=C(N)c1ccccn1
Reactant: N=C(N)c1ccncc1
Product: Nc1ccnc(-c2ccccn2)n1

Procedure:
Following the procedure described in Example A-1 but using in place of isonicotinamidine a molar equivalent quantity in the appropriate pyridine carboxamidine, i.e., Q--C(=NH)NH2, the 4-amino-2-Q-pyrimidines of Examples A-10 through A-13 are obtained:
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[N:13]=[CH:12][N:11]([CH2:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])=[CH:32][CH:31]=1>>[OH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[N:13]=[CH:12][N:11]([CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][N:38]4[C:46](=[O:47])[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:39]4=[O:48])=[CH:34][CH:35]=3)[CH2:19][CH2:20]2)[N:10]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ncn(CC2CCNCC2)n1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCBr)cc1
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCN2CCC(Cn3cnc(C(O)(c4ccccc4)c4ccccc4)n3)CC2)cc1
Yield: 71 %

Procedure:
The title compound was prepared from diphenyl[1-(piperidin-4-ylmethyl)-1H-1,2,4-triazol-3-yl]methanol (Preparation 26, 778 mg, 2.23 mmol) and 2-{2-[4-(2-bromoethyl)phenyl]ethyl}-1H-isoindole-1,3(2H)-dione (Preparation 11, 800 mg, 2.23 mmol) using the same method as described in preparation 12, to give a white solid, in 71% yield, 1.00 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:17]4=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]4[C@H:15]4[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]34)[CH:19]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: Clc1ccc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)cc1Cl

Procedure:
Using 3,4-dichloro-1-bromobenzene and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 39 as a powder. 1H NMR (CDCl3, 300 MHz) δ 1.82-1.87 (m, 2H), 2.48-2.55 (m, 1H), 2.57-2.64 (m, 1H), 2.81-3.13 (m, 6H), 3.18-3.25 (m, 1H), 3.42-3.47 (m, 1H), 3.57-3.64 (m, 1H), 3.72 (s, 2H), 5.55 (s, 1H), 6.61-6.68 (m, 2H), 6.74 (s, 1H), 6.89 (d, 1H, J=3 Hz), 7.19 (d, 1H, J=9 Hz). LRMS (ES)+: 406 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>CCOC(C)=O>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)o2)c1

Procedure:
Carboxylic acid (145)(58 mg, 0.26 mmol) was coupled to aniline (124)(50 mg, 0.26 mmol) using Method C. During this reaction, partial hydrolysis occurred. The acid was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:20]=[CH:19][N:18]=[C:17]3[C:8]=2[CH:9]=[CH:10][C:11]2[C:16]3=[N:15][CH:14]=[CH:13][C:12]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:3][CH:2]=1>CO.C(Cl)Cl>[C:21]1([C:12]2[C:11]3[C:16](=[C:17]4[C:8](=[CH:9][CH:10]=3)[C:7]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)=[CH:20][C:19]([C:16]3[CH:17]=[CH:8][CH:9]=[CH:10][C:11]=3[CH3:12])=[N:18]4)[N:15]=[C:14]([C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=3[CH3:7])[CH:13]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1-c1cc(-c2ccccc2)c2ccc3c(-c4ccccc4)cc(-c4ccccc4C)nc3c2n1
Yield: 20 %

Procedure:
This yellow compound was prepared in a process analogous to the synthesis of m-TBP. However, the reaction product consisted of mono-substituted and di-substituted bathophenanthroline. O-TBP was obtained after running chromatography in a silica/mixture of methanol/CH2Cl2 (1:1) column as the first eluent in a 20 percent yield. Mono-o-TBP was obtained as the second eluent in a 50 percent yield. 1H NMR (500 MHz, CDCl3), ppm: 7.97 (s, 2H), 7.85 (s, 2H), 7.77 (s, 2H), 7.64-7.59 (m, 4H), 7.95-7.50 (m, 6H), 7.35 (m, 6H), 2.65 (s, 6H). Analysis for o-TBP.⅛CH2Cl2. Found: C, 87.03, H, 5.41, N, 5.23. Calculated: C, 87.51, H, 5.44, N, 5.35.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.CI.[CH3:16]C(C)([O-])C.[K+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([CH3:16])[C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCc2cc(Br)c(F)cc2N1
Agent: [K+]
Solvent: CI
Product: CN1C(=O)CCc2cc(Br)c(F)cc21

Procedure:
In analogy to the procedure described for the preparation of intermediates A-1 [A], 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one was reacted with methyl iodide in presence of potassium tert-butoxide to give the title compound as a white foam. MS: 258.0, 259.9 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[Cl:13][C:14]1[C:21]([Cl:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].O>C1COCC1>[Cl:13][C:14]1[C:21]([Cl:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][C:15]=1[CH:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:17]
Reactant: Brc1ccccn1
Reactant: COc1ccc(C=O)c(Cl)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(O)c2ccccn2)c(Cl)c1Cl
Temperature: -65 °C

Procedure:
29.3 g of 2-bromopyridine in 150 ml of dry THF is added to 75 ml of 2.6M n-butyllithium that was chilled to -65° C. 2,3-dichloro-4-methoxybenzaldehyde (38.0 g) is then added in 300 ml of THF and the reaction mixture allowed to come to room temperature. It is poured into H2O and the crystalline product filtered off, washed with ether and dried to give α-(2,3-dichloro-4-methoxyphenyl)-2-pyridinemethanol, mp 174°-176° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH:14]1C(=O)O[C:17](C)([CH3:21])[O:16][C:15]1=[O:23])([O-:3])=[O:2].C(O)C>N1C=CC=CC=1.[Cu]>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][C:15]([O:16][CH2:17][CH3:21])=[O:23])([O-:3])=[O:2]
Reactant: CC1(C)OC(=O)C(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)C(=O)O1
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 66 h
Yield: 89.8 %

Procedure:
To a solution of 5-(5-nitroindol-3-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.0 g, 0.031 mol) in a mixture of pyridine (80 mL) and absolute ethanol (20 mL) was added 0.1 g of copper powder and the mixture was refluxed under Ar for 2h. After being stirred at room temperature for 66 h the mixture was refluxed for an additional 1 h. The cooled mixture was filtered and the filtrate was evaporated. The resulting residue was triturated with ether and a little CH2Cl2 to give the title compound (7.3 g, 89%) as a solid,
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=1.[N-:14]=[N+]=[N-].[Na+]>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[CH3:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[O:5][CH2:4][CH2:3][CH2:2][NH2:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(OCCCCl)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(OCCCN)cc1C
Yield: 97 %

Procedure:
9.05 (45.6 mnol) of 1-chloro-3-(3,4-dimethylphenoxy)- propane obtained in step 1 was dissolved in 200 ml of toluene. To the resulting solution were added 14.8 g of NaN3, 2.9 g of n-Bu4NBr and 15.2 g of KI and the mixture was refluxed For 24 hours. The reaction mixture was washed with water and concentrated under a reduced pressure. The resulting residue was purified by chromatography (ethyl acetate: hexane=1:10) to obtain 9.04 g (yield 97%) of the title compound as a brown oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH2:9])[CH3:2].Cl.[C:11](Cl)(Cl)=[O:12]>CO>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]=[C:11]=[O:12])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCC1CCCCC1N
Agent: Cl
Solvent: CO
Product: CCC1CCCCC1N=C=O
Temperature: 110 °C

Procedure:
To a solution of 2-ethylcyclohexylamine (0.61 mmol) in methanol was added HCl (4.0 M in dioxane, 0.152 mL), and concentrated to give a residue. Phosgene solution (20% in toluene, 6.0 mL) was added, and the reaction was heated at 110° C. overnight. Toluene and excess of phosgene were removed in vacuo to give a residue.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCc1cc(C)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1cc(C)c([N+](=O)[O-])cc1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a stirred mixture of 2-ethyl-4-methylbenzoic acid (compound 48.2, 2 g, 12.18 mmol, 1.00 equiv) in sulfuric acid (30 mL) at −10° C. was added dropwise a solution of nitric acid (1.6 g, 16.50 mmol, 2.08 equiv) in sulfuric acid (10 mL). After stirring for 30 min at −10° C., 200 mL of H2O/ice was carefully added and the resulting mixture was extracted with 50 mL of ethyl acetate. The organic phase was washed with 2×50 mL of brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by re-crystallization from ethyl acetate/petroleum ether in the ratio 1:10 to yield 1.0 g (37%) of 2-ethyl-4-methyl-5-nitrobenzoic acid as a light-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:27]=[C:26]([C:28](=[O:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:25]=[C:24]([NH2:35])[CH:23]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[C:30]([NH:29][C:28]([C:26]1[CH:27]=[C:22]([C:21]2[C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[CH:3][C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=4)=[C:6]([C:16]([NH:18][CH3:19])=[O:17])[C:5]=3[CH:20]=2)[CH:23]=[C:24]([NH:35][S:43]([CH3:42])(=[O:45])=[O:44])[CH:25]=1)=[O:34])([CH3:31])([CH3:32])[CH3:33]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cc(N)cc(C(=O)NC(C)(C)C)c3)cc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(-c3cc(NS(C)(=O)=O)cc(C(=O)NC(C)(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
To a solution of 6-amino-5-(3-amino-5-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (100 mg) and pyridine (0.170 mL) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (72.4 mg) slowly at 0° C. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was concentrated and the residue was purified by preparative HPLC to give 5-(3-(tert-butylcarbamoyl)-5-(methylsulfonamido)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide 4 (92 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:15])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2].[Cl:23][CH2:24][C:25](=O)[CH3:26]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:25]([CH3:26])[CH2:24][Cl:23])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: CC(=O)CCl
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Product: CC(CCl)=NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-nitro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with chloropropanone to give 7-nitro-2-[(2-chloro-1-methylethylidene)-hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.CC1C=CC(S([CH2:23][N+:24]#[C-])(=O)=O)=CC=1.C(O[K])(C)(C)C>COCCOC.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[CH:7]([C:23]#[N:24])[CH2:6][CH2:5]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCc2cc(Cl)cc(Cl)c21
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CCc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5,7-dichloro-1-indanone (2.24 mmol) and TosMIC (6.71 mmol) in 25 mL 1,2-dimethoxyethan and 1 mL EtOH was added tBuOK (6.71 mmol) at 5° C. The cooling bath was removed and the reaction mixture was stirred at RT for 1 h. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC using Hept/EtOAc (7/3) gives the desired compound as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH:15]([O:26][Si](C(C)(C)C)(C)C)[C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[CH:7][CH:6]=1.F.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:35])[C:4](=[O:34])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH:15]([OH:26])[C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)C(=O)c1ccc(OCCCC(O[Si](C)(C)C(C)(C)C)c2ccc3ccccc3c2)cc1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C(=O)c1ccc(OCCCC(O)c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A solution of rac-4-[4-[[(1,1 -dimethylethyl)dimethylsilyl]oxy]-4-(2-naphthalenyl) butoxy]-alpha-oxobenzeneacetic acid methyl ester (1.0 g) in acetonitrile (22.5 mL) containing 48% aqueous hydrofluoric acid solution (2.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (MgSO4) and evaporated to provide 0.76 g of crude product that was purified by flash chromatography over silica gel (ethyl acetate-hexane; 7:13) to yield 0.554 g of rac-4-[4-hydroxy-4-(2-naphthalenyl)butoxy]-alpha-oxobenzeneacetic acid methyl ester as an oil.