Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][N:20]=3)=[C:13]([N+:28]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Sn].Cl.[OH-].[Na+]>C(O)C>[NH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](/[CH:18]=[CH:17]/[C:14]2[CH:15]=[CH:16][C:11]([N:8]3[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]3)=[CH:12][C:13]=2[NH2:28])=[N:20]1
Reactant: CS(=O)(=O)N1CCN(c2ccc(/C=C/c3n[nH]c4ccccc34)c([N+](=O)[O-])c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)N1CCN(c2ccc(/C=C/c3n[nH]c4ccccc34)c(N)c2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
(E)-3-{2-[4-(4-methanesulfonylpiperazin-1-yl)-2-nitrophenyl]vinyl}-1H-indazole (0.13 g, 0.29 mmol) obtained in Step 2 was dissolved in ethanol (2.0 mL), and the solution was added with tin (73 mg, 0.62 mmol) and concentrated hydrochloric acid (1.0 mL) under ice-cooling, followed by stirring at 40° C. for 1 hour. To the reaction mixture under ice-cooling, 6 mol/L aqueous sodium hydroxide solution was added to neutralize the mixture. Then, the mixture was filtered. The filtrate was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethyl acetate to obtain (E)-2-[2-(1H-indazol-3-yl)vinyl]-5-(4-methanesulfonylpiperazin-1-yl)phenylamine (0.06 g, 52%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:18]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:19][CH2:20][CH3:21]>CC#N>[CH2:18]([CH:22]1[CH2:23][CH:24]2[N:29]([CH2:13][C@@H:12]([CH3:15])[CH2:11][N:6]3[C:5]4[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=4[O:9][CH2:8][C:7]3=[O:10])[CH:27]([CH2:26][CH2:25]2)[CH2:28]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Solvent: CC#N
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2cc(F)ccc21
Yield: 33.7 %

Procedure:
A microwave vial was charged with (S)-7-fluoro-4-(3-Iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20) (0.047 g, 0.13 mmol) and 3-butyl-8-azabicyclo[3,2,1]octane (0.039 g, 0.23 mmol) in MeCN (2 mL) and sealed. After microwave irradiation, 100° C., 60 min, the reaction mixture was purified by cation exchange CC followed by flash CC (SiO2; CH2Cl2/MeOH 50:1) to give the title compound (112KK05) (0.017 g, 33%). 1H NMR (CD3OD) d 7.34-7.30 (m, 1H), 6.80-6.75 (m, 2H), 4.61 (ABq, J=18.8 Hz, J=15.1 Hz, CH2), 4.04 (dd, J=14.3 Hz, J=5.9 Hz, 1H), 3.93 (dd, J=14.3 Hz, J=8.2 Hz, 1H), 3.18-3.10 (m, 2H), 2.36-2.23 (m, 2H), 2.03-1.85 (m, 3H), 1.62-1.45 (m, 5H), 1.36-1.14 (m, 8H), 0.92-0.87 (m, 2 CH2); 13C NMR (CD3OD) d 166.2, 160.4 (d, J=242.3 Hz), 148.1 (d, J=11.9 Hz), 126.3 (d, J=2.9 Hz), 118.1 (d, J=9.7 Hz), 109.8 (d, J=22.9 Hz), 105.7 (d, J=26.5 Hz), 68.6, 62.5, 61.2, 58.3, 46.4, 39.0, 37.9, 32.1, 30.2, 29.0, 27.8, 27.2, 23.9, 17.2, 14.4.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].N[CH:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C@H:24]([CH2:25][C@@H:26]([OH:36])[CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)[CH3:16]>N1C=CC=CC=1>[OH:36][C@H:26]1[CH2:27][CH2:28][C@@:29]2([CH3:30])[C@@H:24]([CH2:23][CH2:22][C@@H:21]3[C@@H:31]2[CH2:32][CH2:33][C@@:34]2([CH3:35])[C@H:20]3[CH2:19][CH2:18][C@@H:17]2[C:15](=[O:4])[CH3:16])[CH2:25]1
Reactant: CC(N)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52.9 %

Procedure:
20-Amino-3β-hydroxy-5α-pregnane was first concentrated from dry pyridine. Trifluoroacetic anhydride (3.0 mL) was then carefully added to 3.04 mmol of crude 20-amino-3β-hydroxy-5α-pregnane resuspended in 5.0 mL dry pyridine. After stirring the reaction mixture at room temperature for 3.5 h, the reaction mixture was partitioned between diethyl ether and 1N aqueous HCl, shaken and separated. The organic layer was successively washed with 1N aqueous HCl, water, saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was refluxed in 15.0 mL methanol for 26 h and then concentrated. The residue was purified by flash chromatography on a 25 mm column using first one column volume of methylene chloride, then one column volume of 5% ethyl acetate in methylene chloride, and then 10% ethyl acetate in methylene chloride as eluants. Isolation and concentration of the product afforded 668 mg (52.9% yield over three steps, from 3β-hydroxy-5α-pregnan-20-one) of product.
Reaction SMILES: [CH:1]([P:3](=[O:6])([OH:5])[OH:4])=O.[NH2:7][CH2:8][C:9]([OH:11])=[O:10]>[Pd]>[CH2:8]([NH:7][CH2:1][P:3]([OH:4])([OH:5])=[O:6])[C:9]([OH:11])=[O:10]
Reactant: NCC(=O)O
Reactant: O=CP(=O)(O)O
Agent: [Pd]
Product: O=C(O)CNCP(=O)(O)O
Yield: 34 %

Procedure:
Reaction of formylphosphonic acid and glycine was carried out in the manner described in Example 16 except that the catalyst was 1% palladium on alumina (0.5 g, 3.2 mm pellets). A 34% yield of glyphosate was obtained.
Reaction SMILES: FC1C=C(C=CC=1)N.ClC1C=CC2C(=C([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)C=CC=2)N=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[NH:28]1[C:27]2[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=2[CH:21]=[CH:20]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Nc1cccc(F)c1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NCCc2[nH]ccc21
Yield: 121.9 %

Procedure:
Prepared according to Example 102, using 3-fluoroaniline (230 μl, 2.069 mmol, Sigma Aldrich), 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 77 mg, 0.259 mmol), and 1.0 M LHMDS, in THF (2069 μl, 2.069 mmol, Sigma Aldrich) and stirring at 25° C. for 30 min. Purification by column chromatography (silica gel: 0 to 100% EtOAc/hexanes) provided 2424(3-fluorophenyl)amino)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (43 mg, 44.6%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91-12.00 (m, 1H) 9.69-9.77 (1H, m) 8.14-8.21 (1H, m) 7.87-7.93 (2H, m) 7.62-7.77 (3H, m) 7.31-7.54 (2H, m) 7.08-7.16 (2H, m) 6.78-6.89 (1H, m) 3.38-3.50 (2H, m) 2.67-2.76 (2H, m). m/z (ESI, +ve) 373.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:43])[NH:22][CH2:23][C@H:24]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:25]([O:27]N1C(=O)CCC1=O)=O)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)CCCCCCCCCCCCCCC(=O)NCCCC[C@H](NC(OC(C)(C)C)=O)C(ON1C(=O)CCC1=O)=O)(C)(C)C.[NH2:92][CH2:93][C@H:94]([NH:98][C:99]([O:101][C:102]([CH3:105])([CH3:104])[CH3:103])=[O:100])[C:95]([OH:97])=[O:96]>CN(C=O)C>[C:1]([O:5][C:6](=[O:44])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:43])[NH:22][CH2:23][C@H:24]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[C:25](=[O:27])[NH:92][CH2:93][C@H:94]([NH:98][C:99]([O:101][C:102]([CH3:105])([CH3:104])[CH3:103])=[O:100])[C:95]([OH:97])=[O:96])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Agent: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NC[C@H](NC(=O)OC(C)(C)C)C(=O)NC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
15-[(S)-2-tert-Butoxycarbonylamino-2-(2,5-dioxo-pyrrolidin-1-yloxycarbonyl)ethylcarbamoyl]pentadecanoic acid tert-butyl ester can be prepared in similar fashion as that described for 15-[(S)-5-tert-butoxycarbonylamino-5-(2,5-dioxopyrrolidin-1-yloxycarbonyl)pentylcarbamoyl]pentadecanoic acid tert-butyl ester using (S)-3-amino-2-tert-butoxycarbonylamino propionic acid, and it can be reacted with (S)-3-amino-2-tert-butoxycarbonylamino propionic acid in DMF at RT for 16 h. After concentrating under vacuum, AcOEt can be added the residue and the mixture can be washed with 0.2 N HCl. The organic phase is then dried over MgSO4 and concentrated under vacuum to yield the crude product, 15-[(S)-2-tert-butoxycarbonylamino-2-((S)-2-tert-butoxycarbonylamino-2-carboxyethylcarbamoyl)ethylcarbamoyl]pentadecanoic acid tert-butyl ester. This can either be used without further purification or purified by flash chromatography.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:11]([OH:20])=[CH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2>ClCCl.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[Cl:1][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:10]([CH3:9])[C:11]=1[OH:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc2ccccc2cc1O
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1O
Temperature: -78 °C
Yield: 78.2 %

Procedure:
To a solution of N-chlorosuccinimide (8.02 g, 60.05 mmol) in dichloromethane (475 mL) at −78° C. was added zirconium(IV)chloride (2.80 g, 12.01 mmol), followed by 3-methyl-naphthalen-2-ol (4A) (9.5 g, 60.05 mmol) under Ar. The reaction mixture was stirred at −78° C. for minutes, the cooling bath was removed and the reaction was stirred at room temperature for 5 h. The reaction was quenched with saturated sodium bicarbonate solution and stirred for 5 minutes. The mixture was diluted with H2O, extracted with dichloromethane (3×) and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 4B as a white solid (9.05 g, 78%).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[O:24][C:23]([O:25]C)=[N:22][CH:21]=2)=[O:19])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1.OC1C=C(C(O)=O)ON=1.Cl>O1CCOCC1>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[O:24][C:23](=[O:25])[NH:22][CH:21]=2)=[O:19])[CH2:9][C@@H:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnc(OC)o1
Agent: Cl
Agent: O=C(O)c1cc(O)no1
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxyoxazole-5-carboxamido)-2-methylpentanoate, intermediate 20, (175 mg, 0.40 mmol) in dioxane (5 mL) is added a solution of 4M HCl in dioxane (501 μL, 2.01 mmol) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture is concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(2-oxo-2,3-dihydrooxazole-5-carboxamido)pentanoate (154 mg). HPLC retention time=1.89 minutes (condition B); MS 423.3 (M+1). 1HNMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=7.1 Hz, 3H) 1.11 (t, J=7.1 Hz, 3H) 1.61 (ddd, J=14.0, 10.2, 4.3 Hz, 1H) 1.81 (ddd, J=13.8, 9.9, 3.9 Hz, 1H) 2.41-2.50 (m, 1H) 2.73 (dd, J=13.3, 7.3 Hz, 1H) 2.83 (dd, J=13.3, 7.3 Hz, 1H) 3.99 (q, J=7.1, 2H) 4.05-4.22 (m, 1 H) 7.26 (d, J=8.1 Hz, 2H) 7.30-7.39 (m, 1H) 7.44 (t, J=7.7 Hz, 2H) 7.53 (s, 1H) 7.58 (d, J=8.3 Hz, 2H) 7.64 (d, J=7.1 Hz, 2H) 8.10 (d, J=8.8 Hz, 1H) 11.25 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].ClCCl.C(Cl)(C(Cl)=O)=O.C[N:24](C)C=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:24])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 5 °C

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed 5-fluoro-2-nitrobenzoic acid (25 g, 135.06 mmol, 1.00 equiv), dichloromethane (400 mL) and N,N-dimethylformamide (0.1 g). This was followed by the addition of (COCl)2 (30 g) dropwise with stirring at 0-10° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in 200 mL of dichloromethane. To this was added ammonia (400 mL) dropwise with stirring at 0-10° C. The resulting solution was stirred for 2 h at room temperature. The solids were collected by filtration. This resulted in 20 g (80%) of 5-fluoro-2-nitrobenzamide as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.81 (s, 1H), 8.00 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]([NH2:22])=[S:21])=[CH:15][CH:14]=1.Cl[CH2:31][C:32](=O)[CH3:33].C(=O)(O)[O-].[Na+]>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]2[S:21][CH:31]=[C:32]([CH3:33])[N:22]=2)=[CH:17][CH:18]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1csc(C(c2ccc(OCc3ccc4ccccc4n3)cc2)C2CCCCCC2)n1

Procedure:
1.5 g (0.0037 mol) of the compound from Example III and 5 ml of chloroacetone are heated with 10 ml of water at 100° C. in an oil bath for 30 minutes. The mixture is then neutralised with sodium bicarbonate solution and extracted with methylene chloride. After the extract has been dried with sodium sulphate, it is concentrated to dryness in vacuo, and the residue is recrystallised in diisopropyl ether.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][C:8]=1[OH:30])C.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:5][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14]2[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)=[CH:9][C:8]=1[O:30][CH2:2][C:3]#[N:4]
Reactant: CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1OCC#N
Temperature: 100 °C
Yield: 35.8 %

Procedure:
Bromoacetonitrile (134 mg, 1.12 mmol), compound 41 (150 mg, 0.449 mmol), and K2CO3 (185 mg, 1.34 mmol) were combined with dry acetone (5 mL) in a sealed microwave vessel. The mixture was heated at 100° C. for 20 min in a Personal Chemistry Emrys Optimizer microwave. The reaction was allowed to cool to room temperature and the solids filtered. The solids were rinsed twice with acetone and the solvent removed in vacuuo. The crude mixture was purified using flash column chromatography with dichloromethane as the eluent to give 60 mg (36%) of 45 as a colorless solid (36%). 1H NMR (400 MHz, CDCl3): δ 0.88 (s, 6H), 0.91 (s, 6H), 1.25 (s, 2H), 1.77 (s, 2H), 1.90 (s, 2H), 2.20 (s, 3H), 4.62-4.68 (s, 2H), 6.78 (d, J=8.1 Hz, 1H) 6.75-7.05 (m, 2H), 7.09-7.25 (m, 5H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:10](Br)[CH:11]=[CH2:12]>CN1C(=O)CCC1>[CH2:10]([N:2]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:1])[CH:11]=[CH2:12]
Reactant: C=CCBr
Reactant: CNc1cccc(O)c1
Solvent: CN1CCCC1=O
Product: C=CCN(C)c1cccc(O)c1
Temperature: 80 °C
Yield: 137.9 %

Procedure:
To 3-(N-methylamino)phenol (10 g, 80 mmol), dissolved in 80 ml of NMP, was added allyl bromide (9.8 ml, 113 mmol) via syringe. The yellow solution was heated to 80° C. for 4 hours. The reaction mixture was poured into distilled water (200 ml) and saturated aqueous sodium bicarbonate solution was added. Extraction with diethyl ether (3×200 ml), drying over anhydrous magnesium sulfate, filtration and concentration in vacuo yielded 18.0 g of 3-(N-allyl-N-methylamino)phenol as a viscous green tinted oil. Vacuum distillation at 1 tort (110°-120° C.) yielded 10.5 g (80%) as a pale yellow oil.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1.N([O-])=O.[Na+].[BrH:31]>O>[Br:31][C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1
Reactant: Br
Reactant: Nc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.0 g (14.55 mmoles) of 5-amino-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole, (Example 64), in 25 ml of 40% hydrobromic acid, cooled at 5°, was diazotized with a solution of 1.1 g (16 mmoles) of sodium nitrite in 5 ml of water. The reaction mixture was allowed to warm to room temperature, filtered, and then added dropwise to a solution of 4.0 g (27.7 mmoles) of cuprous bromide in 25 ml of 48% hydrobromic acid. After standing overnight, dilution with water gave a precipitate which was collected by filtration. The solids were extracted with methylene chloride, and the organic layer washed with 1N aqueous sodium hydroxide solution was then with water. The extract was dried over potassium carbonate and evaporated to give 1.2 g of 5-bromo-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]-cyclohepta[1,2-c]pyrrole as an oil; nmr spectrum δ 1.0-4.0 (m, 19); 6.8-7.5 (m, 7).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1Br)[C:18]([OH:20])=[O:19])[CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:47])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1)[CH3:26]>>[CH2:1]([O:8][C:9]([N:11]([CH2:14][C:15]1[CH:16]=[C:17]([C:18]([OH:20])=[O:19])[CH:21]=[CH:22][C:23]=1[C:32]1[CH:31]=[C:30]([CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:47])[CH:35]=[CH:34][C:33]=1[O:36][CH3:37])[CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1cc(C(=O)O)ccc1Br)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(=O)O)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 3-[(benzyloxycarbonyl-ethyl-amino)-methyl]-4-bromo-benzoic acid and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester. M+H is 506.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[CH:4]=1)=[O:2].[OH:14]OS([O-])=O.[K+].Cl.O>CN(C=O)C>[CH3:13][O:12][C:10]([C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([CH3:9])[N:6]=1)[C:1]([OH:14])=[O:2])=[O:11]
Reactant: COC(=O)c1cc(C=O)cc(C)n1
Reactant: O=S([O-])OO
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(=O)O)cc(C)n1
Reaction time: 2 h

Procedure:
To a stirring solution of 216 mg (1.20 mmol) of methyl 4-formyl-6-methylpicolinate in 4 mL of DMF was added 790 mg (1.29 mmol) of Oxone. After about 2 h, 5 mL of 1N HCl and 5 mL of H2O were added, and the aqueous layer was extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, and concentrated. The desired product (2-(methoxycarbonyl)-6-methylisonicotinic acid) was used in the next reaction without further purification.
Reaction SMILES: C1C(=O)N(O[C:9]([CH2:11][CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:14]2=[O:15])=[O:10])C(=O)C1.[NH2:20][CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>CN(C)C=O.C(Cl)Cl>[C:14]1(=[O:15])[N:13]([CH2:12][CH2:11][C:9]([NH:20][CH2:21][CH2:22][CH2:23][Si:24]([O:31][CH2:32][CH3:33])([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])=[O:10])[C:18](=[O:19])[CH:17]=[CH:16]1
Reactant: O=C(CCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCO[Si](CCCNC(=O)CCN1C(=O)C=CC1=O)(OCC)OCC
Reaction time: 22 h
Yield: 118.8 %

Procedure:
3-Maleimidopropionic acid N-hydroxysuccinimide ester (18) (4.0 g, 15.03 mmol, 1.0 equiv.) was dissolved in N,N-dimethylformamide (75 mL) and 3-aminopropyltriethoxysilane (17) (5.06 mL, 15.03 mmol, 1 equiv.) was added and the reaction mixture was allowed to stir for 22 hours. An aliquot (0.15 mL) was removed by syringe, concentrated in vacuo, and the resulting oil was analyzed by 1H NMR spectroscopy. The oil was consistent with desired product. The reaction mixture was then concentrated in vacuo at 50-55° C. and the residue obtained was dissolved in CH2Cl2 (75 mL), washed with water (3×50 mL) and brine (50 mL), filtered through granular Na2SO4, and concentrated under reduced pressure in vacuo to provide 6.65 g (>100% due to residual N,N-dimethylformamide) of the crude maleimide-silane (19) as a light yellow oil. Crude (19) was used without purification. 1H NMR (300 MHz, CDCl3) δ 6.65 (s, 2H), 6.00 (s, 1H), 3.77 (q, J=7 Hz, 6H), 3.70 (m, 2H), 3.17 (m, 2H), 2.46 (m, 2H), 1.56 (m, 2H), 1.18 (t, J=7 Hz, 9H), 0.57 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 170.36, 169.28, 134.09, 58.35, 41.77, 34.56, 34.21, 23.20, 18.20, 7.65. FB-MS (pos): [M+H]+ 373 (373.2 calcd).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:23])[CH3:22]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH:27]2[CH2:28][CH2:29][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:25][CH2:26]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(C)N1CCC(N)CC1
Product: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-isopropylpiperidin-4-amine (21.5 mg, 0.12 mmol). The title compound was obtained as a solid (10.7 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.63 (1H, d), 8.50 (1H, s), 3.56 (1H, m), 2.77 (2H, m), 2.67 (1H, m), 2.13 (2H, m), 1.76 (2H, m), 1.43 (2H, m), 0.95 (6H, d). MS m/z: 475.15, 477.13 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1.[CH3:23][C:24]([CH3:26])=O>>[CH:24]([NH:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1)([CH3:26])[CH3:23]
Reactant: CC(C)=O
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Product: CC(C)NC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21

Procedure:
reacting 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine with acetone to yield 9-((3aR,4R,6R,6aR)-6-((isopropylamino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine;