Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].[N:22]#[C:23]Cl.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:23]#[N:22])=[C:15]([Cl:21])[CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8]
Reactant: CC(C)(c1cc(Cl)c(O)c(Cl)c1)c1cc(Cl)c(O)c(Cl)c1
Reactant: N#CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(c1cc(Cl)c(O)c(Cl)c1)c1cc(Cl)c(OC#N)c(Cl)c1
Yield: 99.7 %

Procedure:
36.6 g (0.1 mol) of 2,2-bis-(3,5-dichloro-4-hydroxyphenyl)-propane are suspended in 500 ml of water and 400 ml of methylene chloride. After cooling to about 0° to 3° C, 20 ml (0.4 mol) of cyanogen chloride are added. A solution of 10.6 g of Na2CO3 in 50 ml of water is added dropwise over the course of 90 minutes, with vigorous stirring, in such a way that the pH value of the reaction mixture is constantly kept in the range between 7.5 and 8.5. Thereafter, 1 N NaOH is added in such a way that a pH value of the reaction mixture of about 8.0 is maintained, and persists as the final value. Thereafter, the organic phase is separated off, washed with 100 ml of water and concentrated at room temperature. 39 g (99% of theory) of 2-(3,5-dichloro-4-hydroxyphenyl)-2-(3,5-dichloro-4-cyanatophenyl)-propane are obtained as the residue.
Reaction SMILES: [CH:1]1([C:11]([O:13]C)=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:10][O:9][C:7]([CH:4]1[CH2:5][CH2:6][CH:1]([C:11]([OH:13])=[O:12])[CH2:2][CH2:3]1)=[O:8]
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
To a stirred solution of dimethyl cyclohexane-1,4-dicarboxylate (10.2 g, 51 mmol) in a mixture of 2:1:1 tetrahydrofuran/methanol/water (52 mL) was added lithium hydroxide (2.13 g, 51 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was partitioned between diethyl ether and water. The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid, and the precipitate collected, and dried under vacuum to afford 4-(methoxycarbonyl)cyclohexanecarboxylic acid (7.4 g): 1H NMR (300 MHz, CDCl3) δ 3.68 (s, 3H), 2.33-2.27 (m, 2H), 2.11-2.06 (m, 4H), 1.50-1.43 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([O-:31])=[O:30]>>[CH:18]([N:13]1[C:12]([C:35]2[CH:36]=[CH:37][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][CH:34]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: CC(C)n1nc2c(c1-c1ccc([N+](=O)[O-])cc1)CCNCC2
Yield: 17.7 %

Procedure:
The title compound (34 mg) was prepared according to Example 189 using 274 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 321 mg of 4-nitrophenylboronic acid. MS (ESI): exact mass calculated for C16H20N4O2, 300.16. found, m/z 301.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.42-8.40 (m, 2H), 7.62-7.60 (m, 2H), 4.37 (m, 1H), 3.43-3.41 (m, 2H), 3.21-3.18 (m, 2H), 2.82-2.79 (m, 2H), 1.41 (d, J=8.2 Hz, 6H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.FC1C(F)=C(C#CC2C=CC(N)=CC=2)C(F)=C(F)N=1.[O:25]=[C:26]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]#[C:55][C:56]2[C:61]([F:62])=[C:60]([F:63])[N:59]=[C:58]([F:64])[C:57]=2[F:65])=[CH:50][CH:49]=1)[C@@H:27]([NH:39]C(=O)OC(C)(C)C)[CH2:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C>N1C=CC=CC=1.Cl>[ClH:3].[ClH:3].[NH2:39][C@@H:27]([CH2:28][CH2:29][CH2:30][NH2:31])[C:26]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]#[C:55][C:56]2[C:61]([F:62])=[C:60]([F:63])[N:59]=[C:58]([F:64])[C:57]=2[F:65])=[CH:50][CH:49]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Solvent: c1ccncc1
Product: NCCC[C@H](N)C(=O)Nc1ccc(C#Cc2c(F)c(F)nc(F)c2F)cc1
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
L-Boc-Orn(Boc)-OH (0.25 g, 0.75 mmol) was dissolved in 1.5 mL of pyridine. The solution was cooled to −25° C. and phosphorus oxychloride (0.12 g, 0.75 mmol) was added dropwise with vigorous stirring. After stirring for 15 min. at −25° C., 4-((perfluoropyridin-4-yl)ethynyl)aniline, (13a) (0.10 g, 0.38 mmol) in pyridine (1.5 mL) was added slowly. The reaction mixture was stirred for 0.5 h at −25° C. and then at room temperature for 10 h. The reaction mixture was quenched with ice/water and extracted with EtOAc. The organic layer was washed with sat. NaHSO4 three times, dried with Na2SO4 and was concentrated in vacuo. The crude product was subjected to chromatography with MeOH:CH2Cl2=1:80 and the Boc-protected product was obtained in 23% yield. (S)-Di-tert-butyl (5-oxo-5-((4-((perfluoropyridin-4-yl)ethynyl)phenyl)amino)pentane-1,4-diyl)dicarbamate (100 mg, 0.17 mmol) was dissolved in gaseous HCl saturated MeOH (4 mL) at 0° C. and the solution was stirred for 10 hours at room temperature. The precipitated product (40 mg, 51%) was obtained by filtration: 1H-NMR (300 MHz, CD3OD) δ 7.82 (d, J=9.0 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H), 4.15 (t, J=6.3 Hz, 1H), 3.14 (t, J=8.4 Hz, 2H), 2.02-2.09 (m, 2H), 1.83-1.88 (m, 2H)
Reaction SMILES: C([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][O:24][Si](C(C)(C)C)(C)C)[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>C(#N)C>[ClH:21].[Cl:22][C:17]1[CH:16]=[C:15]([CH:13]2[CH:12]([CH2:23][OH:24])[O:11][CH2:10][CH2:9][NH:8][CH2:14]2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CC(C)(C)[Si](C)(C)OCC1OCCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC#N
Product: Cl
Product: OCC1OCCNCC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
To a solution of (6RS,7SR)-4-benzyl-7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane (250 mg) in acetonitrile (1.5 mL) was added 1-chloroethyl chloroformate (0.0786 mL), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure. To the residue was added methanol (1.5 ml), and the reaction mixture was stirred at 60° C. for 3 hr. The solvent was evaporated under reduced pressure. The residue was solidified with diisopropyl ether, and the obtained crude crystals were recrystallized from ethanol/ether/water to give the title compound (76.8 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([OH:8])[CH2:7][CH2:6][CH2:5]1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([I:19])=[CH:17][N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=2[N:15]=1>C1COCC1>[Cl:9][C:10]1[N:11]=[C:12]([O:8][C:4]2([CH3:3])[CH2:7][CH2:6][CH2:5]2)[C:13]2[C:18]([I:19])=[CH:17][N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=2[N:15]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: CC1(O)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(Oc2nc(Cl)nc3c2c(I)cn3COCC[Si](C)(C)C)CCC1
Temperature: 60 °C
Yield: 77 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 2.0 equiv) in dry THF (0.45 M) under a nitrogen atmosphere was added a solution of 1-methylcyclobutanol (1.2 equiv) in dry THF (0.27 M) at 0° C. The reaction mixture was stirred at 30° C. for 30 min before a solution of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv) in dry THF (0.23 M) was added and the resulting reaction mixture was heated at 60° C. for 2 h. After the reaction was completed, the reaction mixture was quenched with saturated aqueous ammonium chloride solution. The organic solvent was removed under vacuum and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure. The product was purified by silica gel chromatography (2% ethyl acetate in petroleum ether) to afford the title compound (77% yield) as a yellow oil. MS (ESI) m/z 494.2 [M+H]+.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.75 h
Yield: 96.6 %

Procedure:
To a solution of (R)-4-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (61.2 mg, 0.160 mmol) in THF (1.6 mL) and methanol (0.2 mL), aqueous 1M NaOH solution (0.638 mL, 0.638 mmol) is added at room temperature. After stirring for 45 minutes, the reaction is quenched with aqueous 0.1 M HCl and is extracted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-4-(biphenyl-4-yl)-3-(3-carboxypropanamido)butanoic acid (54.9 mg). HPLC retention time=1.33 minutes (condition A); MS (m+1)=356.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.40-2.56 (m, 6H) 2.83-2.94 (m, 2H) 4.43-4.50 (m, 1H) 7.29-7.32 (m, 3H) 7.41 (t, 2H, J=7.7 Hz) 7.53-7.60 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])C.[OH-].[Na+]>C(O)C>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:15]([C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([F:13])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:27])=[O:3])=[O:26])=[C:19]([F:25])[CH:20]=1
Reactant: CCOC(=O)COc1cc(F)c(C)cc1C(=O)NCc1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)NCc2ccc(Br)cc2F)c(OCC(=O)O)cc1F
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A stirring solution of (2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (0.72 g, 1.62 mmol) in ethanol (8.1 mL, 0.2 M) was placed in an ice bath and treated with aq NaOH (1.25 M, 7.8 mL, 9.73 mmol). The mixture was gradually allowed to warm to room temperature and after two hours the mixture was concentrated under reduced pressure, diluted with ethyl acetate, and treated with 2 N HCl (10 mL). The separated organic layer was washed with saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated to afford [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid (0.66 g, 98%) as a white solid: mp 169° C.; Rf 0.22 (20% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 9.00 (bd t, J=5.3 Hz, 1H), 7.76 (d, J 9.6 Hz, 1H), 7.49 (d, J=9.6 Hz, 1H), 7.39-7.33 (m, 2H), 7.04 (dd, J1=11.4 Hz, J2=1.4 Hz, 1H), 4.84 (d, J=1.8 Hz, 2H), 4.48 (bd s, 2H), 2.17 (s, 3H); ESI-LC/MS m/z calcd for C17H14BrF2NO4: 413.0; found 412 (M−1)−. Anal. calcd for C17H14BrF2NO4: C, 49.30; H, 3.41; N, 3.38. Found C, 49.32; H, 3.43; Br, 3.32.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=[O:3])[CH3:2]>C(O)C.[Pt].[H][H]>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC1Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CC(=O)N1CCCC1Cc1ccc(N)cc1

Procedure:
Hydrogenate 3.3 g of 1-acetyl-2-(4-nitrobenzyl)pyrrolidine with platinum/hydrogen in ethanol. Filter the catalyst from the hydrogenated product and concentrate the filtrate to obtain the title compound as a yellowish liquid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:21]([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)NC(C)C
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)N(C(=O)c1ccc(Br)cc1)C(C)C
Reaction time: 8 h

Procedure:
A mixture of 4-bromobenzoic acid (200 g, 1 mol) and thionyl chloride (300 mL) was refluxed for 3 hours. The mixture was concentrated in vacuo to remove excessive thionyl chloride, and then azeotroped with toluene (3×). The crude residue was dissolved in CH2Cl2 (2 L) and cooled in ice-water bath. To the resulting solution was added dropwise a mixture of triethylamine (330 mL, 2.38 mol) and diisopropylamine (168 mL, 1.19 mol) over 1 hour. The solution was allowed to stir overnight, and then washed with 1N HCl, followed by brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 4-bromo-N,N-diisopropylbenzamide. LRMS calc'd for (C13H18BrNO) [M+H]+, 284; found 284.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:10]([CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[O:27]1[C:31](B(O)O)=[CH:30][C:29]2[CH:35]=[CH:36][CH:37]=[CH:38][C:28]1=2>>[O:27]1[C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[CH:30]=[C:31]1[C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[C:12]([CH3:13])=[C:11]([C:14]([N:16]2[CH2:20][CH2:19][CH:18]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH2:17]2)=[O:15])[C:10]([CH3:26])=[N:9]1
Reactant: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(Br)c3)c2C)C1
Reactant: OB(O)c1cc2ccccc2o1
Product: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3ccccc3-c3cc4ccccc4o3)c2C)C1
Yield: 68 %

Procedure:
In analogy to the procedure described in Example 14C], [1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and benzo[b]furan-2-boronic acid gave the title compound in 68% yield as light brown foam. MS: 457.3 (MH+).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:19]=[CH:18][CH2:17][C:16]2[C:9]=1[CH:10]=[C:11]1[C:15]=2[CH:14]=[N:13][N:12]1[CH2:20][C@@H:21](O)[CH3:22].C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:31]([C@H:21]([CH3:22])[CH2:20][N:12]1[C:11]2=[CH:10][C:9]3[C:16]([CH2:17][CH:18]=[CH:19][C:8]=3[O:7][CH3:6])=[C:15]2[CH:14]=[N:13]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=C2C=c3c(cnn3C[C@H](C)O)=C2CC=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1=C2C=c3c(cnn3C[C@@H](C)N=[N+]=[N-])=C2CC=C1
Yield: 75.5 %

Procedure:
0.4 ml (4.92 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 0.6 g (2.46 mmol) of (S)-1-(7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 1.4 ml (9.84 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.32 g (4.92 mmol) of sodium azide and the reaction mixture was heated to 80° for 15 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 80 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 0.5 g (75%) of (R)-1-(2-azido-propyl)-7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazole was obtained as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][OH:13].N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])[CH3:21]>C(Cl)Cl>[C:20]([Si:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[O:13][CH2:12][C:11]#[C:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([CH3:22])([CH3:19])[CH3:21]
Reactant: OCC#CCCOC1CCCCO1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC#CCCOC1CCCCO1)(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
A solution of compound 3 and imidazole in CH2Cl2 was treated with TBDPSCl dropwise at 0° C. for 2 h. The reaction mixture was diluted with CH2Cl2 (300 mL) and washed with water (200 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified with 10% EtOAc in hexanes by silica gel column chromatography to give 18.0 g of compound 4 (42.6 mmol, 96% yield): 1H NMR (CDCl3) δ 7.80˜7.64 (m, 4H), 7.49˜7.34 (m, 6H), 4.63 (t, J=3.6 Hz, 1H), 4.31 (t, J=1.9 Hz, 2H), 3.93˜3.83 (m, 1H), 3.77 (dt, J=9.7, 7.1 Hz, 1H), 3.55˜3.44 (m, 2H), 2.48 (tt, J=7.1, 2.1 Hz, 2H), 1.89˜1.46 (m, 6H), 1.06 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].[N+:19]([O-:22])([OH:21])=[O:20]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([N+:19]([O-:22])=[O:20])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2n1
Product: CCOC(=O)c1ncc2[nH]c3c([N+](=O)[O-])cccc3c2n1
Product: CCOC(=O)c1ncc2[nH]c3ccc([N+](=O)[O-])cc3c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.325 g of 5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 3) is stirred in 6 ml of 65% strength nitric acid for 15 minutes at room temperature, then for one hour at 70° C. Thereafter the reaction mixture is poured into ice water and extracted with ethyl acetate. The combined ethyl acetate extracts are evaporated; the evaporation residue is chromatographed on silica gel with a mixture of equal parts of methylene chloride and acetone, thus obtaining 0.012 g of 6-nitro-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (mp 318°-325° C.) and 0.023 g of 8-nitro-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 304°-306° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:13]O)[CH2:9][N+:8]([O-:21])=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:6]=2[CH:29]=1.C=O.O.[C:33]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:33]=[N:13][C:12]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[C:10]3[CH2:9][N+:8]([O-:21])=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:6]=2[CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2NC(C(=NO)N2CCOCC2)C1
Agent: C=O
Solvent: O
Solvent: CCO
Product: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-n2cnc(N3CCOCC3)c2C1

Procedure:
A mixture of 3 g (7.1 mmole) of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine 4-oxide, 0.6 g (20 mmole) of paraformaldehyde, 100 ml of ethanol and 250 mg of paratoluene sulfonic acid hydrate was heated to reflux for 16 hours. The crude product obtained after the usual workup was chromatographed over 60 g of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The clean fractions of product were combined and evaporated. The residue was crystallized from ether and recrystallized from ethyl acetate/hexane for analysis to yield end product as yellow crystals with mp 200°-203° C.
Reaction SMILES: [NH4+].[C:2]([C:4](=[CH2:10])[CH2:5][CH2:6][C:7]([O-:9])=[O:8])#[N:3].Cl>>[C:2]([C:4](=[CH2:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:3]
Reactant: C=C(C#N)CCC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Product: C=C(C#N)CCC(=O)O
Temperature: -78 °C
Yield: 60 %

Procedure:
A 100-mL portion of the filtrate containing the 4-cyano-4-pentenoic acid ammonium salt product mixture described above was adjusted to pH 2.7 with 6 N HCl, then saturated with sodium chloride and extracted with 4×100 mL of ethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, and the volume of the combined extracts reduced to 100 mL by rotary evaporation at reduced pressure at 28° C. To the ether solution was added 200 mL of hexane, and the resulting solution cooled to -78° C. The resulting white solid which crystallized was isolated by rapid vacuum filtration and washing with 100 mL of cold (5° C.) hexane. Residual solvent was removed under high vacuum (150 millitorr) to yield 9.80 g (60% isolated yield) of 4-cyano-4-pentenoic acid (m.p. 26.5-27.0° C., stored at -20° C.).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:11]([C:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[I:1]/[CH:2]=[CH:3]/[CH:4]([O:10][C:20]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(O)/C=C/I
Reactant: COc1ccc(CC(Cl)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCC(/C=C/I)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 14.92 g. (0.0588 mole) of 1-iodo-trans-1-octen-3-ol (Example 955) and 18.2 g. (0.0588 mole) of p-anisyldiphenylmethyl chloride in 165 ml. of dry pryidine is heated at 60°C. for 18 hours under an inert atmosphere. The mixture is cooled and the solvent is evaporated in vacuo. The residue is partitioned between ether and water, and the organic phase is washed with water and saturated brine, dried (MgSO4), and evaporated. The residue is chromatographed upon 300 g. of Florisil packed in hexane and the product is eluted with hexane and 4:1 hexane-benzene the yield a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][N:18]=1>>[CH3:23][C:22]1[C:17]([O:1][C:2]2[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)=[N:18][CH:19]=[C:20]([S:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH:21]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: Cc1cc(S(=O)(=O)c2ccccc2)cnc1Cl
Product: Cc1cc(S(=O)(=O)c2ccccc2)cnc1Oc1cc(CC(=O)O)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (ii).