Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1C=C[CH:4]=[CH:3][CH:2]=1.[CH:7]([SiH:10]([CH:26]([CH3:28])[CH3:27])[C:11]1[CH:25]=[CH:24][C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])=[CH:13][CH:12]=1)([CH3:9])[CH3:8].C(CCO)#N.C(N(CC)CC)C>C(Cl)(Cl)Cl.O>[C:2]([CH2:3][CH2:4][O:22][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][NH:17][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([SiH:10]([CH:7]([CH3:9])[CH3:8])[CH:26]([CH3:28])[CH3:27])=[CH:25][CH:24]=1)#[N:1]
Reactant: c1ccncc1
Reactant: CC(C)[SiH](c1ccc(C(=O)NCCCC(=O)O)cc1)C(C)C
Agent: N#CCCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[SiH](c1ccc(C(=O)NCCCC(=O)OCCC#N)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
A condensing agent of N,N-bis (2-oxo-3-oxazolidinyl)-phosphnic acid chloride BOP-Cl (1.5 g, 6.1 mmol) was added to pyridine solution (20 mL) dissolving 4-[4-(diisopropylsilanyl)benzoylamino]butanoic acid (3) (1.3 g, 4.1 mmol), 2-cyanoethanol (548 μL, 8.1 mmol) and triethylamine (828 μL, 6.1 mmol). The resulting mixture was stirred for 3 hours at a room temperature and mixed with water (5 mL). Five minutes later, it was diluted with chloroform (200 mL) and extracted three times with 5 wt % aqueous solution (150 ml) of sodium hydrogen carbonate. An organic layer was collected and dehydrated with anhydrous sodium sulfate and filtered so that the resulting solvent was distilled out under a reduced pressure. The resulting crude product was then purified by silica gel column chromatography. After eluted with chloroform having 0-3% methanol gradient, the solvent was distilled out to give a desired product (1.2 g, 79%). Its NMR data are as follows:
Reaction SMILES: Br[CH2:2][C:3](OCC)=[O:4].[F-].[K+].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[OH:20]>CN(C=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]2[NH:10][C:3](=[O:4])[CH2:2][O:20][C:12]=2[CH:13]=1)([O-:19])=[O:18]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCOC(=O)CBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, ethyl bromoacetate (7.2 ml, 65 mmol) was added to a solution of anhydrous potassium fluoride (10 g, 172.1 mmol) in 50 ml anhydrous DMF. The solution was stirred for 30 minutes at room temperature. 2-Amino-5-nitrophenol (Aldrich, 10 g, 65 mmol) was then dissolved in 25 ml of DMF and added dropwise to the reaction with stirring. After the final addition the reaction was warmed to 70 degrees and stirred for 16-24 hours. The reaction was then poured into 300 mls of an ice/water mixture with stirring. A yellow precipitate was formed immediately. The solid was filtered off and dried in vacuo. The product was recrystallized from hot THF. Collected 8.3 g (72.5%) of tan crystals: m.p. 227-230; 'H NMR (300 MHz, DMSO) δ 4.752 (s, 2H, CH2), 7.0835 (d, J=8.73, Hz, 1H, ACH), 7.769 (d, J=2.44 Hz, 1 H) 7.9185 (dd, J=2.525, 8.705 Hz, 1H, ACH); 13C NMR (300 MHz, DMSO) δ 66.560, 111.344, 115.776, 118.738, 134.464, 142.643, 142.861, 164.891. Mass spectrum (EI) m/z 194 M+
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:28]4[C:19](=[CH:20][C:21]5[O:26][CH2:25][CH2:24][O:23][C:22]=5[CH:27]=4)[O:18][CH2:17]3)[C:9]2=[O:29])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([C:28]3[C:19](=[CH:20][C:21]4[O:26][CH2:25][CH2:24][O:23][C:22]=4[CH:27]=3)[O:18][CH2:17]2)[C:9]1=[O:29]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (89%) as a colorless solid: mp>250° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ10.57 (s, 1H), 7.24 (ddd, J=7.7, 7.7, 1.0 Hz, 1H), 7.09 (d, J=6.9 Hz, 1H), 6.96 (dd, J=7.5, 7.5 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.16 (s, 1H), 4.73 (d, J=9.2 Hz, 1H), 4.60 (d, J=9.2 Hz, 1H), 4.20-4.15 (m, 2H), 4.13-4.08 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ178.3, 154.6, 144.0, 141.7, 137.7, 132.5, 128.7, 123.7, 122.2, 121.4, 111.1, 109.8, 98.6, 79.4, 64.2, 63.6, 57.6; MS (ES+) m/z 296.3 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C@H:10]([CH2:25][CH2:26][CH3:27])[C@H:11]([CH3:24])[C:12](N1C2C=CC=CC=2OC1=O)=[O:13]>O1CCCC1>[CH2:1]([NH:8][C:12](=[O:13])[C@@H:11]([CH3:24])[C@H:10]([OH:9])[CH2:25][CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC[C@@H](O)[C@H](C)C(=O)n1c(=O)oc2ccccc21
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Product: CCC[C@@H](O)[C@H](C)C(=O)NCc1ccccc1
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
Benzylamine (0.6 mL, 5.5 mmol) is added dropwise to a solution of N-[(2S*,3R*)-3-hydroxy-2-methylhexanoyl]-2-benzoxazolinone (1.31 g, 5.0 mmol) in 10 mL of tetrahydrofuran. A mildly exothermic reaction ensues. After 15 min, the solvent is evaporated. The residue is redissolved in 50 mL of CH2Cl2 and washed successively with equal volumes of 1 N HCl, 1 N NaOH, water, and brine. After drying over MgSO4, the solution is evaporated to yield 1.12 g (95% yield) of the product as a white solid which was recrystallized from ethyl acetate/hexanes as white needles, mp 114–115° C. 1H-NMR (d6-DMSO, 400 MHz) δ 8.27 (t, J=6, 1 H), 7.30 (m, 2 H), 7.22 (m, 3 H), 4.49 (d,J=6, 1 H), 4.27 (dd,J=6,15, 1 H), 4.20 (dd,J=6,15, 1 H), 3.44 (m, 1 H), 2.20 (q, J=7, 1 H), 1.43 (m, 1 H), 1.22 (m, 3 H), 1.04 (d,J=7,3 H), 0.79 (t,J=7,3 H). 13C-NMR (d6-DMSO, 100 MHz): 175.2, 140.2, 128.6, 127.6, 127.1, 71.8, 46.9, 42.2, 37.6, 19.0, 14.7, 14.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[NH:24])[NH:22][OH:23])=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47](Cl)=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>CC(=O)OCC>[C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:24]=[C:34]([C:35]3[CH:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=4)=[CH:37][CH:36]=3)[O:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Reactant: COC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(Cc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 43 %

Procedure:
Prepared using General Procedure 20. To a stirring solution of methyl 2-((tert-butoxycarbonyl)(4-(N-hydroxycarbamimidoyl)benzyl)amino)acetate INT-75 (786 mg, 2.33 mmol) and DIEA (448 μL, 2.56 mmol) in dioxanes (15 mL) was added 4′-methyl-[1,1′-biphenyl]-4-carbonyl chloride (591 mg, 2.56 mmol), at room temperature. After 30 min the reaction mixture was heated to 120° C. for 3 h. The reaction mixture was diluted with EA (150 mL) and washed with brine (100 mL). The organics were concentrated in vacuo and the crude product purified by chromatography (MeCN/DCM) to afford 518 mg (43%) of methyl 2-((tert-butoxycarbonyl)(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)amino)acetate INT-76 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[CH:32]1([CH2:38][C@H:39]([NH:51][C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=2)=[O:53])[C@@H:40]([OH:50])[CH2:41][C:42]([NH:44][C@H:45]2[CH2:49][CH2:48][NH:47][CH2:46]2)=[O:43])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1>[CH:32]1([CH2:38][C@H:39]([NH:51][C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=2)=[O:53])[C@@H:40]([OH:50])[CH2:41][C:42]([NH:44][C@H:45]2[CH2:49][CH2:48][N:47]([C:27]([C@@H:11]3[CH2:10][C@H:9]([S:8][CH2:7][C:6]4[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:13][N:12]3[C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])=[O:28])[CH2:46]2)=[O:43])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=O)C[C@H](O)[C@H](CC4CCCCC4)NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.47 g) in anhydrous tetrahydrofuran (30 ml), N,N'-carbonyldiimidazole (0.59 g) was added, followed by stirring at 30° C. for one hour. To the reaction mixture, a solution of (3S)-3-[(3S,4S)-5-cyclohexyl-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)aminopentanoylamino]pyrrolidine (1.38 g) in anhydrous tetrahydrofuran (30 ml) was added. The reaction mixture was treated in a similar manner to that described in Referential Example 18-(1), whereby 2.43 g of the title target compound were obtained as an amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[CH:9]1.[Cl:21]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:21][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(=O)c2c(ncn2-c2ccccc2Cl)n(C)c1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(nc(Cl)n2-c2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
7-(2-Chlorophenyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (138 mg) and N-chlorosuccinimide (78 mg) were suspended in N,N-dimethylformamide (1 ml). The reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 151 mg of the title compound.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]1[C:17]([CH3:18])=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([CH3:19])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:20]([N:9]([CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]1[CH:11]=[C:12]([CH3:19])[C:13]([CH:14]2[O:29][CH2:28][CH2:27][O:15]2)=[CH:16][C:17]=1[CH3:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C1OCCO1
Yield: 97.2 %

Procedure:
To a 500 mL round-bottomed flask was added 4-dibenzylamino-2,5-dimethylbenzaldehyde hydrochloride (11.5 g, 31.4 mmol) and toluene (150 mL) and the resulting mixture was stirred until the salt completely dissolved. The reaction flask was then purged with dry nitrogen for 5 minutes. Ethylene glycol (5.25 mL, 94.2 mmol) and p-toluenesulfonic acid (760 mg, 6.2 mmol) were added and the resulting mixture was heated at 60° C. to 80° C. for about 20 hours. The solvent was then removed slowly (over about 40 minutes) at 40° C. on a rotary evaporator. Toluene (100 mL) was added to the residue and the solvent was again removed slowly at 40° C. on a rotary evaporator. This process was repeated using another aliquot of toluene (100 mL) and the mixture was evaporated to dryness. Ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate (100 mL) were added to the residue and the layers were separated. The organic layer was washed with brine (50 mL) and then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide crude dibenzyl-(4-[1,3]dioxolan-2-yl-2,5-dimethyl-phenyl)amine (11.4 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=1[OH:17])([CH3:7])[CH3:6].C(OCC)(=O)C>C(O)(=O)C>[CH:14]([C:10]1[CH:11]=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=[C:8]([CH:5]([CH3:7])[CH3:6])[C:9]=1[OH:17])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1cc([N+](=O)[O-])cc(C(C)C)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
78.3 mmol (4.93 g) of fuming nitric acid are added dropwise to a solution, cooled to 0° C., of 53.9 mmol (9.62 g) of 2,6-diisopropylphenol in 350 ml of acetic acid. The reaction mixture is stirred at 0° C. for 1 hour 30 minutes and is then poured into a mixture of ethyl acetate and ice. The organic phase is isolated and then washed with water. After drying and evaporating off the solvent, an oily residue is recovered which is purified by chromatography on silica gel using a petroleum ether: ethyl acetate mixture 9:1 as eluant.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][CH2:11][CH2:12][O:13][N:14]1C(=O)C2C(=CC=CC=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[NH2:14][O:13][CH2:12][CH2:11][NH:10][C:9](=[O:25])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Solvent: ClCCl
Product: NOCCNC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of benzyl(2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate (9.36 g, 27.50 mmol) described in Reference Example 10 in methylene chloride (51 mL) was gradually added 9.8M methylamine methanol solution (8.50 mL), followed by stirring for 2 hours. The reaction solution was distilled off under reduced pressure, and methylene chloride (50 mL) and water (80 mL) were added, followed by adjusting to pH 1 with 5M hydrochloric acid, aqueous layer separation, and further washing with methylene chloride (50 mL). To the resulting aqueous layer was added methylene chloride (50 mL), followed by adjusting to pH11 with 5M sodium hydroxide, organic layer separation, and further extracting the aqueous layer with methylene chloride (50 mL) twice. The combined organic layers were washed with 50% potassium carbonate aqueous solution, followed by drying over anhydrous potassium carbonate, and distilling off the solvent under reduced pressure. The resulting residue was subjected to silica gel column chromatography (ethyl acetate) to afford 5.61 g of the title compound (yield 97%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][C:13](OC(C)=O)=[O:14]>CN(C1C=CN=CC=1)C>[CH3:10][C:8]([O:11][C:13](=[O:14])[CH3:12])([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1C(C)(C)O
Agent: CN(C)c1ccncc1
Product: CC(=O)OC(C)(C)c1cccnc1C
Temperature: 100 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
2-(2-methyl-pyridin-3-yl)-propan-2-ol (1.30 g, 8.61 mmol) and DMAP (30 mg) were combined in Ac2O (8 mL) and stirred at 100° C. for 16 hours. Following removal of the solvent under reduced pressure, the brown residue was quenched with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (5×60 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a yellow oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH, 95:5, v/v) afforded acetic acid 1-methyl-1-(2-methyl-pyridin-3-yl)-ethyl ester as a white crystalline solid (1.25 g, 75%). 1H NMR (CDCl3) δ 1.80 (s, 3H), 2.05 (s, 3H), 2.66 (s, 3H), 7.12 (dd, 1H, J=9.0, 6.0 Hz), 7.62 (dd, 1H, J=9.0, 3.0 Hz), 8.39 (dd, 1H, J=6.0, 3.0 Hz).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[O:26][CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccccc1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CC3)n(Cc3ccccc3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 2-(1-benzyl-5,6-difluoro-1H-benzoimidazol-2-yl)-5-chloro-phenol (Example 48, intermediate a) and bromomethyl-cyclopropane (CAS Reg. No. 7051-34-5). Colorless powder (70%). MS (Turbo Spray): m/z=425.3 (M+H).
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:21][C:4]1[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[CH:15]=2)[N:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Temperature: 250 °C

Procedure:
Diethyl({[4-(methyloxy)phenyl]amino}methylidene)propanedioate (100 g, 0.34 mol) was taken up in Dowtherm (500 mL) and heated at 250° C. for 1.5 h; 75% conversion. The reaction solution was cooled, treated with hexanes (750 mL) and cooled to 0° C. in ice bath. The brown solid was filtered off and washed with hexanes (2×) and dried under vacuum to give 60 g (71%).
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([C:34]([F:37])([F:36])[F:35])[C:5]=1[OH:38])(=[O:3])[CH3:2].[N-:39]=[N+:40]=[N-:41].[Na+].Cl.C(N(CC)CC)C>>[OH:38][C:5]1[C:6]([C:34]([F:36])([F:35])[F:37])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:17]3[CH:24]=[CH:23][CH:22]=[C:19]([C:20]4[N:39]=[N:40][NH:41][N:21]=4)[CH:18]=3)=[CH:12][CH:11]=2)[CH:32]=[CH:33][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(C(F)(F)F)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(-c4nn[nH]n4)c3)cc2)c(C(F)(F)F)c1O
Yield: 96.2 %

Procedure:
Employing the procedure of Example 1 using 3-[[4-(4-acetyl-3-hydroxy-2-trifluoromethyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (384 mg, 0.731 mmol), sodium azide (475 mg, 7.31 mmol), and triethylamine hydrochloride (1.01 g, 7.31 mmol) to yield the title compound as a tan solid (400 mg, 96%): 1H NMR (CD3CN) δ1.44-1.91 (m, 6H), 2.56 (s, 3H), 3.44 (m, 1H), 3.78 (m, 1H), 4.66 (q, 1H), 5.23 (d, 2H), 5.91 (d, 1H), 6.73 (dd, 1H), 7.39-7.62 (m, 5H), 7.89-8.08 (m, 3H), 13.75 (s, 1H).
Reaction SMILES: ClCCC[C:5]([O:18]C)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].COC(C1C=CC(OC)=CC=1)C(OC)=O.ClCCCI>>[OH:18][CH:5]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(CCCCl)(OC)c1ccc(OC)cc1
Agent: COC(=O)C(OC)c1ccc(OC)cc1
Agent: ClCCCI
Product: COC(=O)C(O)c1ccc(OC)cc1

Procedure:
246 mg of a mixture of methyl 5-chloro-2-methoxy-2-(4-methoxyphenyl)valerate with methyl methoxy-(4-methoxyphenyl)acetate was obtained from methyl hydroxy-(4-methoxyphenyl)acetate (724 mg) and 1-chloro-3-iodopropane (0.56 ml) by the same method as in Examples 85 and 86. Then, the ester mixture was hydrolyzed and amidated with tert-butyl carbazate according to the method in Examples 85 and 86 to obtain 32 mg of tert-butyl N′-[5-chloro-2-methoxy-2-(4-methoxyphenyl)pentanoyl]hydrazinecarboxylate and 122 mg of tert-butyl N′-[2-methoxy-2-(4-methoxyphenyl)acetyl]hydrazinecarboxylate.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[Br:13][C:14]1[CH:15]=[C:16]([C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[C:36]#[N:37])=[N:22]S(C(C)(C)C)=O)[CH:17]=[CH:18][C:19]=1[F:20].Cl>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:21]2([C:7]3[CH:8]=[N:9][CH:10]=[N:11][CH:12]=3)[C:29]3[C:30](=[C:31]([F:35])[CH:32]=[CH:33][CH:34]=3)[C:36]([NH2:37])=[N:22]2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Brc1cncnc1
Reactant: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NC1=NC(c2cncnc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Reaction time: 0.75 h
Yield: 56.9 %

Procedure:
n-Butyllithium (0.136 mL, 0.34 mmol) was slowly added to 5-bromopyrimidine (50 mg, 0.31 mmol) in THF (1.0 mL) at −78° C. under argon atmosphere. The reaction mixture was stirred for 45 min. N-((3-Bromo-4-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (111 mg, 0.26 mmol) in THF (1.0 mL) was added dropwise and the resulting reaction mixture was stirred at −78° C. for 1 h, and then allowed to reach room temperature. The reaction was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were washed with brine and concentrated in vacuo. The residue was dissolved in methanol (2.0 mL) and hydrochloric acid (2.0 M in diethyl ether, 0.393 mL, 0.79 mmol) was added at room temperature. The mixture was stirred over night, and then concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate (saturated) and ethyl acetate (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 0 to 10% (3.5 M ammonia in methanol) in dichloromethane gave the title compound (59.4 mg, 56% yield). MS (ES+) m/z 401, 403 [M+1]+.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOC(C)=O.CCCCCC>C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(Br)cc3c2CC1
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: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(c1ccccc1)N1CCc2[nH]c3ccc(-c4ccccc4)cc3c2CC1
Yield: 55.7 %

Procedure:
A mixture of 3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.477 g, 4.00 mmol) and tetrakis(triphenylphosphine)palladium (0.462 g, 0.40 mmol) in dimethoxyethane (15.0 mL) and a solution of phenylboronic acid (0.585 g, 4.80 mmol) in dimethoxyethane (5.0 mL) and sodium carbonate (2 M, 12.0 mL) were reacted in a manner similar to Preparation 1. Column chromatography (silica gel, 60% EtOAc/hexane) afforded 0.817 g (56%) of the title compound as a solid: mp 78-79° C.; 1H NMR (300 MHz, CDCl3) δ 8.10-7.85, 7.71-7.57, 7.43-7.29, 7.18-7.05, 4.16-4.04, 3.70-3.65, 3.20-3.05, 2.95-2.80; MS (ESI+) m/z 367 (M++H).