Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]=[C:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1.C1C[O:36]CC1>>[C:20]([O:19][C:17]([NH:13][CH2:14][CH2:15][CH:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:12]([OH:36])=[O:11])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: Clc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)(C)OC(=O)NCCC(Cc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 9.4 %

Procedure:
LHMDS (28.3 mL, 28.3 mmol) was diluted into THF (90 mL) and cooled to −78° C. tert-Butyl 2-oxopyrrolidine-1-carboxylate (5.00 g, 27.0 mmol) was dissolved into THF (35 mL) and added to the LHMDS over a 5 minute period at −78° C. The reaction was allowed to stir for 45 minutes, and then a THF (35 mL) solution of 1-(bromomethyl)-4-chlorobenzene (5.82 g, 28.3 mmol, 1.05 equiv) was added. The reaction was allowed to stir at −78° C. for 1 hour, and then warmed to room temperature over 3 hours. The mixture was quenched with the addition of a 3M LiOH solution (90 mL) and stirred for 48 hours at room temperature. The reaction was then diluted with water and washed with ethyl acetate. The aqueous layer was acidified with 3M HCl and extracted several times with ethyl acetate. The combined organic fractions were washed with water, dried over MgSO4, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (60:40 hexanes:ethyl acetate) to give 4-(tert-butoxycarbonylamino)-2-(4-chlorobenzyl)butanoic acid (0.84 g, 9.4%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=3[OH:17])[N:9]=[C:5]2[CH:4]=1.C(N(CC)CC)C.[CH2:29]([CH:31]([CH2:35][CH2:36][CH2:37][CH3:38])[C:32](Cl)=[O:33])[CH3:30].O>C1(C)C=CC=CC=1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:32](=[O:33])[CH:31]([CH2:29][CH3:30])[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:12][C:11]=3[OH:17])[N:9]=[C:5]2[CH:4]=1
Reactant: Nc1ccc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c1
Reactant: CCCCC(CC)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC(CC)C(=O)Nc1ccc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c1

Procedure:
To a mixture of 4 g of 5-trifluoromethyl-2-(2-hydroxy-4-aminophenyl)-2H-benzotriazole and 1.4 g of triethylamine in 75 mL of toluene is added dropwise a mixture of 2-ethylhexanoyl chloride in 125 mL of toluene. The resulting mixture is treated with 100 mL of water and the crude product formed is purified by column chromatography to give 1.9 g of the title compound melting at 179-181° C. The structure is confirmed by nmr.
Reaction SMILES: [CH:1]1([C@H:6]([OH:29])[C@H:7]([N:18]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][N:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN.CCOCC>CCO>[NH2:18][C@@H:7]([C@H:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[OH:29])[CH2:8][N:9]([CH3:17])[C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(C[C@H]([C@@H](O)C1CCCC1)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CN(C[C@@H](N)[C@@H](O)C1CCCC1)C(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
2-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(N-methyl-N-(t-butoxycarbonyl)amino)propan-2-yl)isoindoline-1,3-dione (0.7961 mg, 2.0 mmol) was dissolved in a minimal volume of EtOH (20 mL) and hydrazine monohydrate (0.5 mL, 10.3 mmol) was added. The solution was heated at 55° C. for 45 min and at reflux for 2 h. A white solid (precipitation of the hydrazone) resulted and the reaction was cooled to rt. Ether (50 mL) was added and the reaction was filtered through #1 Whatman filter paper. The filtrate was stripped and the residue was stirred in ether (15 mL) for 1 h, filtered, and stripped to give tert-butyl (2R,3S)-2-amino-3-cyclopentyl-3-hydroxypropyl-methylcarbamate (199.7 mg, 36%). LC-MS (3 min) tR=1.10 min, m/z=272 (M+).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:34][N:33]=2)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: NN
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 72.7 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-methylsulfonylphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (101 mg, 0.23 mmol) in DMF (2.5 ml) was added hydrazine monohydrate (80%, 28 μl, 0.87 mmol, 3.8 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(4-methylsulfonylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (72 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7](O)=[O:8])[N:6]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7]([Cl:17])=[O:8])[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)O
Product: CCOC(=O)c1sc(Cl)nc1C(=O)Cl

Procedure:
2-Chloro-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (Intermediate 7, 1 g, 4.24 mmol) was dissolved in thionyl chloride (5 mL) and refluxed for two hours. It was then concentrated to give the desired product (light brown oil, 1 g). NMR (CDCl3): 1.37 (t, 3H), 4.39 (q, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][CH2:22][N:21]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:20][C:19]2[N:40]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2].[C:41]1([C:57](O)=[O:58])[C:54]2[C:55]3=[C:56]4[C:51](=[CH:52][CH:53]=2)[CH:50]=[CH:49][CH:48]=[C:47]4[CH:46]=[CH:45][C:44]3=[CH:43][CH:42]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[C:41]1([C:57]([N:25]2[CH2:24][CH2:23][CH2:22][N:21]([S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:20][C:19]3[N:40]=[C:15]([CH:16]=[CH:17][CH:18]=3)[CH2:14][N:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:27][CH2:26]2)=[O:58])[C:54]2[C:55]3=[C:56]4[C:51](=[CH:52][CH:53]=2)[CH:50]=[CH:49][CH:48]=[C:47]4[CH:46]=[CH:45][C:44]3=[CH:43][CH:42]=1
Reactant: O=C(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCNCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cccc(n2)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(c1ccc2ccc3cccc4ccc1c2c34)N1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cccc(n2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Yield: 85.5 %

Procedure:
The title compound was prepared following the procedures illustrated above in Example 75 using 3,10-bis(2-nitrobenzenesulfonyl)-3,6,10,16-tetraazabicyclo-[10.3.1]hexadeca-1(16),12,14-triene (0.59 g, 1.0 mmol), 1-pyrenecarboxylic acid (0.25 g, 1.0 mmol), DCC (0.21 g, 1.0 mmol), HOBT (0.14 g, 1.0 mmol) and 4-methylmorpholine (0.15 g, 1.5 mmol) in 20 mL of CH2Cl2 and 10 mL of DMF. The compound was purified by flash chromatography on a silica gel column using 200:1 CH2Cl2—MeOH as an eluent to give 0.7 g (86%) of the title compound as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:16]2[CH:24]=[CH:25][CH:26]=[C:15]2[CH2:14]1)=[O:12])[C:5]([NH2:7])=[O:6].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>>[CH3:29][N:30]([CH:32]=[N:7][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][N:16]3[CH:24]=[CH:25][CH:26]=[C:15]3[CH2:14]2)=[O:12])=[C:2]([Cl:1])[CH:3]=1)[CH3:31]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Product: CN(C)C=NC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1

Procedure:
The title compound was prepared in the same manner as described in Example 80, employing 3-chloro-4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzamide (1.83 g) and dimethylformamide dimethylacetal (5.3 ml), MS (EI), m/z::420 (M)+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:21])[CH2:5]1.CS(O[CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)(=O)=O>CN(C=O)C>[C:28]12([CH2:27][N:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[N:7]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:6](=[O:21])[CH2:5][C:4]3=[O:3])[CH2:29][CH:30]3[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]3)[CH2:37]1)[CH2:35]2
Reactant: CS(=O)(=O)OCC12CC3CC(CC(C3)C1)C2
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1CC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
Sodium hydride 80% dispersion in oil (0.07 g) was added portionwise to a solution of 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.5 g) in DMF (50 ml). The reaction mixture was stirred for 30 min, then a solution of 1-adamantylmethyl methanesulfonate (0.537 g) in DMF (3 ml) was added. The reaction mixture was stirred at 120° for 7 h and at 23° for 15 h, then concentrated. The residue was diluted with ethyl acetate (100 ml) washed with brine (2×30 ml) and water (50 ml), dried and concentrated "in vacuo". The crude product was purified by flash chromatography (eluting with CH-EA 1:1) to give the title compound as a white foam (0.15 g). T.l.c. CH-EA (1:1), Rf =0.42.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:18][CH2:19][CH3:20].C([Li])CCC.CCCCCC.CN(C)[CH:34]=[O:35]>O1CCCC1>[F:10][C:9]([F:12])([F:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:34]=[O:35])=[C:3]([CH2:18][CH2:19][CH3:20])[CH:4]=1)([OH:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CN(C)C=O
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
To a nitrogen purged 3-necked flask was added 2-(4-bromo-3-propylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.74 mmol, 1 g) in anhydrous tetrahydrofuran (15 mL). The solution was cooled to −78° C. before the addition of n-butyl lithium in hexane (2.5M, 8.22 mmol, 3.29 mL). The mixture was stirred at −78° C. for 15 minutes before the drop wise addition of N,N-dimethylformamide (3.01 mmol, 0.220 g). The mixture was stirred at −78° C. for 10 minutes and was then allowed to warm to room temperature and stir for 30 minutes. The mixture was quenched with water (10 mL) and diluted with ethyl acetate (100 mL). The organic phase was separated, washed with water (2×50 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with 10% ethyl acetate/90% heptane) to afford the title compound (417 mg). MS (ESI) m/z 313.3 [M−H]−
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:4]1.[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:57]>CO>[ClH:57].[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][CH2:2][C@@H:3]3[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]4[C:20]5[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=5)[CH:14]=[CH:13][C:12]4=[O:23])[CH2:4]3)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: COc1ccc2ccc(=O)n(CCN3C[C@H](CN)[C@H](O)C3)c2c1
Reactant: ClCCl
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3C[C@H](CNCc4cc5c(cn4)OCCO5)[C@H](O)C3)c2c1
Product: Cl
Reaction time: 18 h
Yield: 45 %

Procedure:
1-{2-[(3S,4S)-3-(Aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-(methyloxy)-2(1H)-quinolinone (94 mg, 0.296 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (54 mg, 0.326 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 18 h then sodium triacetoxyborohydride (197 mg, 0.884 mmol) was added and stirred for 1 h. The reaction mixture was concentrated and purified to obtain the free base of the title compound as a pale oil (62 mg, 45%) after column:chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)C=O)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].CO[CH:29]([O:32][CH3:33])[O:30][CH3:31].C(=O)(O)[O-].[Na+]>CO>[CH3:33][O:32][CH:29]([O:30][CH3:31])[C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])[CH:20]=1
Reactant: CC(C)(C)C(=O)Oc1cccc(C=O)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cccc(OC(=O)C(C)(C)C)c1
Reaction time: 1 h

Procedure:
Four hundred mg of p-toluenesulfonic acid dissolved in 25 ml of methanol was added, with stirring, to the 3-pivaloyloxy-benzaldehyde of Example I. Trimethylorthoformate (224 ml; 2.05 mol) was then added dropwise. The minor exotherm that resulted was allowed to proceed unchecked while the mixture was stirred for 1 hour. One half gram of sodium bicarbonate was added, and the flask was placed on the rotary evaporator (bath temperature 40° C.) to remove all volatiles. The resulting oil was passed through a short silica gel column under nitrogen pressure to give an orange-brown oil which was pumped under vacuum (1.0 mm Hg) with stirring to yield 426 g of crude 3-pivaloyloxybenzaldehyde dimethyl acetal. Infrared analysis revealed no aldehyde carbonyl absorption (1695 cm-1).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]2[O:14][C:15](=[O:23])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)[CH:10]=[CH:9][C:8]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44])C.O.[OH-].[Li+].S(=O)(=O)(O)[OH:50]>C1COCC1.O>[C:15]([C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[CH2:18][C:13]([C:11]1[CH:10]=[CH:9][C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:41]=[CH:40][C:34]3[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[CH2:42][CH2:43][CH3:44])=[C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:45])[CH:12]=1)=[O:50])([OH:14])=[O:23]
Reactant: O=S(=O)(O)O
Reactant: CCCc1c(OCCCCCOc2ccc(-c3cc4ccccc4c(=O)o3)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCCCOc2ccc(C(=O)Cc3ccccc3C(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Reaction time: 47 h
Yield: 79.6 %

Procedure:
A mixture of 0.145 g (0.24 mmol) of 2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]-5-(1-oxo-1H-2-benzopyran-3-yl)benzenepropanoic acid ethyl ester in 5 mL of THF and 5 mL of water was treated with 29.8 mg (0.71 mmol) of lithium hydroxide monohydrate and the mixture was stirred for 47 hrs. After being acidified with 16 mL of 3N aqueous sulfuric acid, the resulting mixture was worked up in the usual manner. The crude product was crystallized from hexane-ethyl acetate to give 0.114 g (79.6%) of the title compound as a white solid, mp 178°-182° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
69.1 g (0.5 mol) of para-hydroxybenzoic acid were first dissolved in 200 ml of water and 300 ml of isopropanol and this solution was adjusted to a pH of 10.5 at 20 to 25° C. using 87.4 g of NaOH solution (32% strength by weight aqueous solution, 0.7 mol). Metered into this solution then at a pH of 10.5, over the course of three hours, were 70.2 g (0.5 mol) of benzoyl chloride. The pH was held at 10.5 using 40.5 g of NaOH solution (32% strength by weight aqueous solution, 0.324 mol), and the temperature was held at 20 to 25° C. The batch was stirred for one hour thereafter. Subsequently the reaction mixture was adjusted to a pH of 7 at 20 to 25° C. using 5.3 g of HCl solution (32% strength by weight aqueous solution) and adjusted to a pH of 1.5 to 3 at 65 to 70° C. using 60 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to room temperature (25° C.) and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 119.1 g (98.3% of theory). According to HPLC and NMR measurement, the product was free from benzoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8](I)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cu](C#N)[C:14]#[N:15]>CN(C)C=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:14]#[N:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(I)cc(C(=O)O)c1N
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cc(C(=O)O)c1N
Temperature: 150 °C
Reaction time: 9 h
Yield: 62.9 %

Procedure:
A mixture of 1.0 g of 2-amino-5-iodo-3-methylbenzoic acid, 0.45 g of copper cyanide and 10 ml of N,N-dimethylformamide was stirred at 150° C. for 9 hours. The reaction mixture was concentrated under reduced pressure. Into the residue, 20 ml of water and 2 ml of ethylenediamine were poured, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was filtered, the filtrate was adjusted to around pH 5 by an addition of concentrated hydrochloric acid, and then extracted with ethyl acetate three times. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure to obtain 0.40 g of 2-amino-5-cyano-3-methylbenzoic acid of the formula:
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]([C:12]1[CH:17]=[C:16]([SH:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:6][C:5]([S:18][C:16]1[CH:15]=[C:14]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:13]([OH:23])=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:17]=1)([CH3:7])[CH2:4][C:2](=[O:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(=O)C=C(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(C)(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
8.48 Grams of mesityl oxide (0.084 moles) is added dropwise to a solution of 21.0 grams of 2,6 di-tert-butyl-4-mercaptophenol (0.088 moles) and one gram of triethylamine in 30 ml of toluene. The mixture is heated at 50°-55° C. for six hours. The solvent is then stripped off under vacuum and the residue retained at 60°-65° C. and 0.20 mm. Hg. for two hours. The residue is dissolved in toluene and purified by flash chromatography using silica gel. The product is isolated from solution by distilling off the volatiles under vacuum to a final pressure of 0.10 mm. Hg for five hours.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH2:17][O:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:23](F)[C:20]=2[C:21]#[N:22])=[CH:12][CH:11]=1>CC(N(C)C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH2:17][O:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:20]=2[C:21]([NH2:22])=[N:7][C:6]([NH2:8])=[N:5]3)=[CH:14][CH:15]=1
Reactant: N=C(N)N
Reactant: COCOCC(COc1cccc(F)c1C#N)c1ccc(Cl)cc1
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: COCOCC(COc1cccc2nc(N)nc(N)c12)c1ccc(Cl)cc1
Temperature: 135 °C
Reaction time: 24 h
Yield: 24.4 %

Procedure:
Guanidine carbonate (792 mg; 4.4 mmol) is suspended in a solution of 2-[2-(4-Chlorophenyl)-3-methoxymethoxypropoxy]-6-fluorobenzonitrile (769 mg; 2.20 mmol) in DMA, and heated to 135° C. for 8 hours. The solution is cooled to RT overnight and placed in a freezer at 4° C. for 24 hours. The resulting black solids are removed by filtration through paper. The filtrate is concentrated under vacuum, and purified by column chromatography (10% MeOH/EtOAc). The collected fractions are dried to give 209 milligrams of 5-[2-(4-chlorophenyl)-3-methoxymethoxy-propoxy]-quinazoline-2,4-diamine.
Reaction SMILES: C(Cl)CCl.C1C=C[C:8]2[N:13](O)N=NC=2C=1.C1[C@H](N)[C@@H]([O:22][C@H:23]2[O:28][C@H:27](CN)[C@@H:26](O)[C@H:25](O)[C@H:24]2[NH2:33])[C@H](O)[C@@H](O)[C@@H]1N.Cl.C=O.C1[C@H]([NH2:46])[C@@H](O)C(O)[C@@H](O)[C@@H]1N>CN(C=O)C>[NH2:33][C@H:24]([C:23]([OH:22])=[O:28])[CH2:25][C:26]1[N:13]=[CH:8][NH:46][CH:27]=1
Reactant: N[C@@H]1C[C@H](N)[C@@H](O)C(O)[C@H]1O
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](N)C[C@@H]2N)[C@H](N)[C@@H](O)[C@@H]1O
Reactant: On1nnc2ccccc21
Agent: C=O
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
Flavin conjugate 46. Flavin carboxylic acid 36 (120 mg, 0.34 mmol; prepared according to well-known methods (Frier, et al. (1997) J. Org. Chem. 62:3520-3528)), DMF (6 mL), EDC (126 mg, 0.66 mmol), HOBt (89 mg, 0.66 mmol), neamine derivative 24 (400 mg, 0.22 mmol), deprotected conjugate hydrochloride 46 (120 mg, 0.13 mmol, 60%): mp 200° C. dec; 1H NMR (400 MHz, D2O) δ 7.47 (s, 1 H, H Fl), 7.43 (s, 1 H, H Fl), 5.69 (d, J1′-2′=3.8 Hz, 1H, H1′), 4.41 (m, 1H, CH2-Fl), 3.88-3.94 (m, 2H, H3′, H4), 3.78-3.87 (m, 2H, CH2O, H5′), 3.52-3.63 (m, 3H, CH2O, H5, H6), 3.33-3.50 (m, 4H, H3, H2′, H6′, H4′), 3.17-3.28 (m, 2H, H6′, H1), 2.92 (t, J=6.9 Hz, 2H, CH2N), 2.32-2.36 (m, 4H, H2eq, CH3 Fl), 2.23 (s, 3H, CH3 Fl), 2.08 (t, 2H, J=7.2 Hz, CH2CO), 1.76 (ddd, J2ax-1=J2ax-3=J2eq-2ax=12.6 Hz, 1H, H2ax), 1.63-1.70 (m, 2H, CH2 chain), 1.45-1.53 (m, 2H, CH2 chain), 1.35-1.45 (m, 2H, CH2 chain), 1.18-1.33 (m, 4H, 2CH2 chain), 1.05-1.15 (m, 4H, 2CH2 chain); 13C NMR (50 MHz, D2O) δ 176.0 (CO), [160.7, 157.3, 150.3, 148.7, 138.7, 134.0, 133.5, 130.5, 130.1, 115.8] (1C Fl), 92.5 (C1′), [82.1, 72.9, 72.2, 71.8, 69.7, 67.8] (6CH nea, CH2O), [52.8, 49.4, 48.5] (3CH nea), 45.2 (CH2N Fl), [39.6, 38.6] (CH2N, C6′), 35.1 (CH2-CO), [28.6, 27.7, 27.4, 25.7, 25.4, 24.8, 24.5, 24.2] (7CH2, C2), 20.3, (CH3), 18.2 (CH3); LRMS (electrospray) m/z=782.4 [M+Na]+, 600.3 [5-modified deoxystreptamine+H]+; HRMS (electrospray) Calcd for C36H57N9O9Na [M+Na]+: 782.4176, found: 782.4178.