Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1C2C=CC(N)=CC=2OC1.[H-].[Na+].CC1C=CC(S([O:23][CH2:24][CH2:25][C:26]([CH3:61])([CH3:60])[CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:37]=[CH:38][N:39](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:40]=2)(=O)=O)=CC=1>CN(C)C=O.CO.C(O)(=O)C>[NH:39]1[CH:40]=[C:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH2:28][CH2:27][C:26]([CH3:60])([CH3:61])[CH2:25][CH2:24][OH:23])[N:37]=[CH:38]1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: Nc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(CCO)CCOc1ccccc1-c1c[nH]cn1
Temperature: 80 °C
Yield: 7 %

Procedure:
The above product was isolated as a side product in the following reaction: To a solution of benzo[d][1,3]dioxol-5-amine (0.447 mmol) in N,N-dimethylformamide (2 mL) was added NaH (0.447 mmol) at room temperature and after stirring for 15 min 3,3-dimethyl-5-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)pentyl 4-methylbenzenesulfonate (0.223 mmol) was added as a solution in N,N-dimethylformamide (1 mL). The reaction was stirred at 80° C. overnite. After cooling to room temperature, the reaction mixture was diluted with methanol (2 mL) and acetic acid (2 mL). The reaction was heated to 80° C. for 3 h, after cooling to room temperature, the reaction mixture was partitioned between dichloromethane (30 mL) and 20% sodium bicarbonate solution (10 mL), the organic layer was separated and the aqueous phase extracted with dichloromethane (3×25 mL). The combined organic extract was dried (Na2SO4) and concentrated to afford the crude. Yield 7%. 1H NMR: 1.10 (s, 6H), 1.24 (s, 1H), 1.62 (t, 2H, J=7.32 Hz), 1.89 (t, 2H, J=7.24 Hz), 3.75 (t, 2H, J=7.44 Hz), 4.16 (t, 2H, J=7.24 Hz), 6.97 (d, 1H, J=8.52 Hz), 7.01 (d, 1H, J=7.52 Hz), 7.21 (m, 1H), 7.51 (s, 1H), 7.69 (s, 1H), 7.78 (d, 1H, J=7.60 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](C2C=CC=CC=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[CH:30]/[C:31]1[CH:36]=[CH:35][C:34]([S:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:12]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1Br
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
2-[2-({4-[(E)-2-(2,4-Difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]-1-([2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole was prepared according to the method of Example 135 Step 2 using 2-(2-bromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (Step 1) in place of (S)-1-(2-iodophenyl)ethanol and Intermediate 2 in place of Intermediate 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=2)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2[CH:27]=[CH:26][C:25]([C:23]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:24])=[CH:30][CH:29]=2)=[CH:3][C:4]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1cc(-c2cc(-c3ccc(C(=O)N4CCOCC4)cc3)cnc2N)nn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and (4-(morpholine-4-carbonyl)phenyl)boronic acid (183 mg, 0.77 mmol) in 1,4-dioxane (10.0 mL)/water (5.0 mL) was added Cs2CO3 (690 mg, 2.12 mmol) at room temperature. The reaction mixture was degassed with argon for 30 min. Then Pd(PPh3)4 (40 mg, 0.03 mmol) was added and allowed to stir at 110° C. for 30 min in CEM micro wave. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude compound. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 5% MeOH in DCM to afford 100 mg (yield: 35.97%) of the title compound as pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:19]=[CH:18][C:17]3[O:20][C:21]4[C:26]([C:27]5([C:35]6[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=6)[C:29]([NH2:36])=[N:28]5)[C:16]=3[CH:15]=2)=[CH:25][C:24]([C:37]2[C:38]([F:43])=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:23][CH:22]=4)[CH2:10][CH2:9]1>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:43][C:38]1[C:37]([C:24]2[CH:25]=[C:26]3[C:27]4([C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29]([NH2:36])=[N:28]4)[C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][O:8][CH2:9][CH2:10]5)[N:19]=[CH:18][C:17]=4[O:20][C:21]3=[CH:22][CH:23]=2)=[CH:42][CH:41]=[CH:40][N:39]=1
Reactant: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3cnc(C4=CCOCC4)cc32)c2ccccc21
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3cnc(C4CCOCC4)cc32)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
A flask containing a solution of 3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,1′-isoindol]-3′-amine 2,2,2-trifluoroacetate (30 mg, 0.051 mmol) and MeOH (4 mL) was evacuated and backfilled with nitrogen. Pd/C (10 weight %, 100 mg, Aldrich) was added and the flask was evacuated and backfilled with H2 gas. The flask was fitted with a balloon filled with H2 gas (1 atm) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was filtered through a pad of celite and the celite was washed with EtOAc. The solvent was removed under reduced pressure and the remaining residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min to obtain the title compound (7.8 mg, 25.9%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].ClC1C=[CH:16][S:15][C:14]=1C(OCCCCCCCC)=O.[C:29]1([CH3:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:14]([S:15][C:16]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:29][CH3:35]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: CCCCCCCCOC(=O)c1sccc1Cl
Reactant: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCSc1nc2ccc(C)cc2c(=O)o1
Reaction time: 2 h
Yield: 5 %

Procedure:
2-Amino-5-methylbenzoic acid (1.51 g, 10 mmol) was dissolved in pyridine (10 ml), and to this was added the crude octyl chlorothiolformate (28 mmol, assuming 100% from the first step) as a solution in toluene. After 2 h, the reaction was diluted with ethyl acetate and washed three times with 1M aqueous HCl, then saturated aqueous sodium bicarbonate, water and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. Crystallisation from hexane gave the title compound (155 mg, 5%): δH (400 MHz, CDCl3) 0.91 (3H, t, J 7.0, Me), 1.30-1.34 (8H, m, 4×CH2), 1.44-1.50 (2H, m, SCH2CH2CH2), 1.79 (2H, qn, J 7.4, SCH2CH2), 2.46 (3H, s, ArMe), 3.16 (2H, t, J 7.3, SCH2), 7.38 (1H, d, J 8.2, ArH), 7.58 (1H, dd, J 8.2, 1.8, ArH), 7.93 (1H, s, ArH); m/z (ES+) 306 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[N:26]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:13]([NH:35][CH2:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:15])=[C:3]([CH3:16])[N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: NCCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc2c(C(=O)NCCCN3CCOCC3)c(C)n(C)c2c1
Yield: 59 %

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid 16c (0.483 g, 2.20 mmole) with 2.0 M oxalyl chloride in CH2Cl2 (2.2 ml, 4.4 mmole) and 3-morpholin-4-ylpropylamine in a manner as previously described for example 16d to give a white solid (0.445 g, 59%). 1H NMR (300 MHz, CDCl3) δ7.60 (1H, d, J=8.6 Hz), 6.82 (1H, dd, J=2.3, 8.6 Hz), 6.77 (1H, d, J=2.3 Hz), 6.71 (1H, s), 3.87 (3H, s), 3.62 (3H, s), 3.57 (6H, m), 2.69 (3H, s), 2.50 (2H, t, J=6.6 Hz), 2.43 (4H, m), 1.81 (2H, m); ESIMS (MH+): 346.20.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4](Br)[CH2:5]Br.CCN(CC)CC.[CH2:16]([NH:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH2:24][N:23]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8]
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: COC(=O)C(Br)CBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To the preheated solution (50° C.) of 2,3-dibromo-propionic acid methyl ester in toluene (40 ml) and Et3N (5.80 ml, 41.6 mmol), was added N,N′-dibenzyl-ethane-1,2-diamine (4.90 ml, 20.8 mmol) dropwise. Resulting white slurry was heated to reflux to a clear solution and the solution was stirred at reflux overnight. After cooled to room temperature, the reaction mixture was extracted with 2N HCl (ca. 500 ml) and the extract was neutralized with 4N NaOH. The aqueous layer was extracted with EtOAc three times. The organic layer was washed with brine, dried over MgSO4, and concentrated to give 1,4-dibenzyl-piperazine-2-carboxylic acid methyl ester (5.73 g, 84.8%) as a colorless oil: HPLC-MS (ESI): Calcd for C20H24N2O2[M+H]+ 325, found: 325.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[N:20]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[N:20]=2)[CH:14]=1)[S:28]([CH3:27])(=[O:30])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCNCc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O

Procedure:
Intermediate 2 from above was treated with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 456.
Reaction SMILES: [O:1]([CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[N+:2]([O-:4])=[O:3].[NH2:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:22]([O:21][C:19]([C:18]1[CH:12]([C:11]2[CH:14]=[CH:15][C:8]([O:7][CH2:6][CH2:5][O:1][N+:2]([O-:4])=[O:3])=[CH:9][CH:10]=2)[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH3:24])[NH:16][C:17]=1[CH3:24])=[O:20])[CH3:23]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1ccc(OCCO[N+](=O)[O-])cc1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(OCCO[N+](=O)[O-])cc1

Procedure:
A solution of 5 g of 4-(2-nitroxyethoxy)benzaldehyde and 6.1 g of ethyl 3-aminocrotonate in 100 ml of ethanol was refluxed for 20 hours.
Reaction SMILES: Br.C(O)(=O)C.CS(O)(=O)=O.C(OC([NH:21][CH2:22][CH2:23][C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[NH:35])[NH2:34])=[CH:29][C:28]=1[C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:25])=O)C1C=CC=CC=1>C(OCC)C>[NH2:21][CH2:22][CH2:23][C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[NH:34])[NH2:35])=[CH:29][C:28]=1[C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:25]
Reactant: N=C(N)c1ccc(OC(=O)CCNC(=O)OCc2ccccc2)c(C(=O)c2ccccc2)c1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: N=C(N)c1ccc(OC(=O)CCN)c(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To 4.0 ml of a 30% hydrogen bromide-acetic acid mixture, was added 1.0 g of 4-amidino-2-benzoylphenyl 3-benzyloxycarbonylaminopropionate methanesulfonate. The mixture was stirred for one hour at room temperature to dissolve the crystals, forming a homogeneous yellow solution. Anhydrous ethyl ether was added to the solution to precipitate a white or pale yellow powder. After removing the supernatant, the residue was washed a few times with ethyl ether to obtain 0.5 g of a hydroscopic powder of 4-amidino-2-benzoylphenyl 3-aminopropionate dihydrobromide.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:17]2[CH2:22][CH2:21][N:20]([C@H:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]3[C:30]([CH3:36])=[N:31][CH:32]=[N:33][C:34]=3[CH3:35])=[O:28])[CH2:19][CH2:18]2)[CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:6][CH:5]=1.[Cl-].[NH4+:40]>>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:17]2[CH2:22][CH2:21][N:20]([C@H:23]([CH3:37])[CH2:24][CH2:25][NH:26][C:27]([C:29]3[C:30]([CH3:36])=[N:31][CH:32]=[N:33][C:34]=3[CH3:35])=[O:28])[CH2:19][CH2:18]2)=[CH:6][CH:5]=1)(=[O:2])[NH2:40]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Agent: [Cl-]
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(C(N)=O)cc2)CC1
Yield: 36.7 %

Procedure:
Using general procedure K with COMPOUND 299 (61 mg, 0.11 mmol) followed by general procedure E with the resulting acid and ammonium chloride (10 mg, 0.18 mmol) afforded COMPOUND 300 as a pale yellow foam (21 mg, 35%, over 2 steps). 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.0 Hz), 1.15-1.25 (m, 1H), 1.54-1.58 (m, 2H), 1.78 (d, 3H, J=9.0 Hz), 2.20-2.23 (m, 1H), 2.53 (s, 6H), 2.60 (td, 1H, J=9.0, 3.0 Hz), 2.86-2.96 (m, 3H), 3.33 (td, 1H, J=9.0, 3.0 Hz), 3.69 (td, 1H, J=9.0, 3.0 Hz), 3.84-3.86 (m, 1H), 3.94 (s, 2H), 6.62 (d, 2H, J=9.0 Hz), 6.99-7.02 (m, 2H), 7.31 (dd, 1H, J=6.0, 3.0 Hz), 7.63 (d, 2H, J=9.0 Hz), 8.68 (d, 1H, J=3.0 Hz), 8.91 (s, 1H). ES-MS m/z 521 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:9]2[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:33][CH:34]=3)[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: N[C@@H]1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of (3R)-1-[bis-(4-chlorophenyl)methyl]-3-aminopyrrolidine (2.05 g, compound obtained in Reference Example 11) and triethylamine (1.35 mL) in methylene chloride (30 mL) was added dropwise 4-(trifluoromethoxy)benzoyl chloride (1.21 mL) under ice-cooling and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water and the mixture is extracted with chloroform (×2). The organic layer was filtered through a NH-silica gel (10 g of Chromatorex NH-silica gel; Fuji Silicia Chem.) and the filtrate was evaporated in vacuo. The crude product was triturated in ethyl acetate/hexane to obtain (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (2.70 g; yield: 83%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17]C)=[C:4]([C:9]2[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.B(Br)(Br)[Br:20]>ClCCl>[BrH:20].[NH2:1][C:2]1[C:3]([OH:17])=[C:4]([C:9]2[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1c(N)cc(C)cc1-c1ccc(C(=O)O)s1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: Cc1cc(N)c(O)c(-c2ccc(C(=O)O)s2)c1
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
5-(3-Amino-2-methoxy-5-methyl-phenyl)-thiophene-2-carboxylic acid 24c (0.26 g, 1 mmol) was dissolved in 20 mL of dichloromethane followed by addition of boron tribromide (5 mL, 35.32 mmol/L). The mixture was reacted at room temperature for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure. The residue was diluted with 30 mL of ethyl acetate and stirred for 0.5 hours. The mixture was filtered and the filter cake was washed with ethyl acetate and dried to obtain the title compound 5-(3-amino-2-hydroxy-5-methyl-phenyl)-thiophene-2-carboxylic acid hydrobromide 24d (0.15 g, yield 45.5%) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]=[O:20])=[CH:11]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=[O:20])=[CH:11]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12
Yield: 92 %

Procedure:
The same procedures used in Example 1 were repeated except for using 2.98 g of 4-chlorobenzyl bromide and 2.00 g of indole-3-carbaldehyde as a starting material to give 3.42 g of 1-(4-chlorobenzyl)indole-3-carbaldehyde as pale yellow crystals. The yield thereof was found to be 92%.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:16])[CH:13]([CH3:15])[CH3:14].CCCCCCC.C(OCC)(=O)C>C(O)(=O)C>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[C:12](=[O:16])[CH:13]([CH3:14])[CH3:15].[OH:5][C:6]1[C:11]([N+:1]([O-:3])=[O:2])=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:16])[CH:13]([CH3:14])[CH3:15]
Reactant: O=[N+]([O-])O
Reactant: CC(C)C(=O)c1ccccc1O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(=O)O
Product: CC(C)C(=O)c1cc([N+](=O)[O-])ccc1O
Product: CC(C)C(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 5 °C

Procedure:
1.6 ml of fuming nitric acid were added, over the course of 20 minutes, to a solution of 4.1 g of 1-(2-hydroxyphenyl)-2-methylpropan-1-one in 25 ml of acetic acid cooled to 5° C. The reaction medium was stirred at ambient temperature for 5 hours (followed by TLC, 10/1 heptane/ethyl acetate). The reaction was stopped before all the 1-(2-hydroxyphenyl)-2-methylpropan-1-one was consumed. The reaction medium was diluted with 70 ml of water and then extracted with ethyl acetate (4:1, 3×50 ml). The organic phases were combined, washed with water (20 ml) and then with a saturated sodium chloride solution (25 ml), and dried over magnesium sulfate. The solvent was evaporated off and the residue was chromatographed on silica. 1.40 g of 1-(2-hydroxy-5-nitrophenyl)-2-methylpropan-1-one and 1.2 g of 1-(2-hydroxy-3-nitrophenyl)-2-methylpropan-1-one were obtained.
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12](=[N:16]O)C(O)=O)([O-:4])=[O:3]>C(O)(=O)C>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]#[N:16])([O-:4])=[O:3]
Reactant: O=C(O)C(Cc1ccccc1[N+](=O)[O-])=NO
Solvent: CC(=O)O
Solvent: O
Product: N#CCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Water (50,000 ml), 2,940 ml of glacial acetic acid and (22.22 moles) of 2-nitrophenylpyruvic acid oxime were charged into a 20 gallon reactor. The stirred suspension was heated over two hours under nitrogen atmosphere to 90° and this temperature was maintained for 2 hours. The dark solution was allowed to cool slowly and was stirred overnight at ambient temperature. The suspension was extracted with 5×4,000 ml of methylene chloride, washed with 3×3,000 ml of water, dried over magnesium sulfate and filtered. The filtrate was treated with activated carbon, filtered and the solvent was removed under reduced pressure. The solid residue was recrystallized from 1,000 ml of isopropanol to give 2-nitrophenylacetonitrile, m.p. 82°-84°.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([C:10]#[N:11])=[C:6]([C:8]#[N:9])[N:7]=1)=[CH2:2].S(OC)(O[CH3:16])(=O)=O>C1COCC1.CCOCC>[CH3:16][N:7]1[C:6]([C:8]#[N:9])=[C:5]([C:10]#[N:11])[N:4]=[C:3]1[CH:1]=[CH2:2]
Reactant: COS(=O)(=O)OC
Reactant: C=Cc1nc(C#N)c(C#N)[nH]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=Cc1nc(C#N)c(C#N)n1C
Temperature: 0 °C
Reaction time: 15 h
Yield: 52.4 %

Procedure:
To a solution of 0.602 g (4.17 mmol) of 2-vinyl-4,5-dicyanoimidazole in distilled THF (15 mL) at 0° C. under nitrogen was added slowly while stirring 0.22 mL (2.32 mmol) of dimethyl sulfate and 0.60 mL (4.30 mmol) triethylaminine via syringe. The reaction solution was allowed to come to room temperature and was stirred for 15 hours. The reaction solution was concentrated down under a stream of nitrogen and dissolved in 10 mL CH2Cl2. This solution was washed twice with a 10% solution of NaOH and twice with a saturated solution of NaCl. CH2Cl2 was stripped off, leaving a brown oil. This oil was dissolved in approximately 1 mL of THF and precipitated out in hexane. The precipitate was vacuum filtered and dried to yield 0.345 g (52.4% yield) of a light brown, fluffy powder. This powder was dissolved in 100 mL of ether and vacuum filtered to remove undissolved particles. 20 mL of hexane was added to the ether solution, and the solution was cooled to 0° C. White, needle-shaped crystals were formed and vacuum filtered.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:10][C:9]=12)=[NH:4].[S:28]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=O)=[CH:34][CH:33]=1)(=[O:31])(=[O:30])[NH2:29]>>[F:17][C:14]([F:15])([F:16])[C:13]1[N:8]2[CH:7]=[N:6][C:5]([C:3]3[N:4]=[C:36]([C:35]4[CH:34]=[CH:33][C:32]([S:28]([NH2:29])(=[O:31])=[O:30])=[CH:40][CH:39]=4)[O:1][N:2]=3)=[C:9]2[N:10]=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH:12]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: N=C(NO)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(-c2nc(-c3ncn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)no2)cc1

Procedure:
The title compound was prepared from N-hydroxy-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxamidine (example B.3) (195 mg, 0.5 mmol) and commercially available 4-sulfamoyl-benzoic acid (101 mg, 0.5 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane) as a yellow solid (61 mg, 22%). MS (ISP) 555.3 [(M+H)+]; mp 303° C.