Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[N:7][CH:8]=[C:9]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1>[Ni].N.CO>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][C:9]([CH2:10][NH2:11])=[C:4]2[CH:3]=[CH:2]1
Reactant: N#Cc1cncc2[nH]ccc12
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cncc2[nH]ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A mixture of 1H-pyrrolo[2,3-c]pyridine-4-carbonitrile (232 mg, 1.62 mmol) and Raney Ni (200 mg) in a solution of ammonia/MeOH (7N, 40 mL) was stirred at RT for 4 h. The reaction mixture was filtered and the wet cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure to afford 236 mg (99.0%) of (1H-pyrrolo[2,3-c]pyridin-4-yl)methanamine as yellow solid: MS (ESI) m/z: 148.3 [M+1]+.
Reaction SMILES: F.[NH:2](C(OCC1C=CC=CC=1)=O)[C@H:3]([C:11]([NH:13][C@H:14]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:51]([NH2:53])=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])=[O:26])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:24])[NH:20][N+]([O-])=O)=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N[C@H](C(O)=O)CCCNC(=N)N.NCC(O)=O.N[C@H](C(O)=O)CC1C=CC=CC=1>>[NH2:2][C@H:3]([C:11]([NH:13][C@H:14]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:51]([NH2:53])=[O:52])[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:41])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:30])=[O:26])[CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:24])=[O:12])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N=C(NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O)N[N+](=O)[O-]
Agent: F
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: NCC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O

Procedure:
In 6-ml. of anhydrous hydrogen fluoride was dissolved 500 mg. of Z-Phe-Arg(NO2)-Gly-Phe-Phe-NH2 and the solution was stirred at -10° C for 40 minutes. The hydrogen fluoride was distilled off and the residue was dissolved in 10 ml. of water. The solution was passed through a column (0.9 × 15 cm) of Amberlite IRA-410(acetate-form) which was washed with water. The effluent was combined with the washings and the combined solution was lyophilized. The procedure yielded 402 mg. of the above-indicated compound. Amino acid analysis: Arg, 1.01; Gly, 0.98; Phe, 2.94 (peptide content 86.2%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[C@H:27]([CH2:28][OH:29])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[C@H:27]([CH:28]=[O:29])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of oxalyl chloride (0.798 mL, 9.15 mmol) in CH2Cl2 (11 mL) at −78° C. is added DMSO (1.08 mL, 15.25 mmol) dropwise (evolution of gas observed) and the mixture stirred at −78° C. for 1.5 h. To this is added a solution of (S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.803 g, 3.05 mmol) in CH2Cl2 (9 mL) and the mixture is stirred at −78° C. for 1.5 h. Triethylamine (3.4 mL, 24.41 mmol) is added and the mixture is stirred for 10 min at −78° C. and then warmed to room temperature for 1.5 h. The mixture is extracted with EtOAc (2×30 mL), washed with 1N HCl (1×35 mL) and extracted again with EtOAc (1×30 mL). The combined organic layers are washed with 1N HCl (2×30 mL) and brine (2×30 mL), dried over Na2SO4 and concentrated to afford the title compound.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][C:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])=[C:9]([CH3:35])[CH:8]=1)C.[Li+].[OH-].O.C1COCC1>CO>[CH3:33][C:31]([CH3:34])([O:30][C:28]([C:19]1([CH:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[CH:8][C:9]=2[CH3:35])=[O:15])[CH2:17][CH2:18]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)COc1ccc(NC(=O)N2CCC(C(=O)OC(C)(C)C)(C3CCNCC3)CC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(OCC(=O)O)ccc1NC(=O)N1CCC(C(=O)OC(C)(C)C)(C2CCNCC2)CC1

Procedure:
In a 25 mL round bottomed flask a solution of ethyl-4-[(4-(1,1-dimethylethoxycarbonyl)-4,4'-bipiperidinyl-1-carbonyl)amino]-3-methylphenoxyacetate (31-4) (100 mg, 0.2 mmol), 1M LiOH, (0.6 mL, 0.6 mmol), H2O (5 mL), THF (5 mL), and MeOH (5 mL) was stirred at ambient temperature 3 h. The reaction was concentrated in vacuo, then dissolved in CHCl3 (20 mL). The CHCl3 extract was washed (1N HCl, H2O, and brine), dried (NaSO4), filtered, and concentrated to yield 4-[(4-(1,1-dimethylethoxycarbonyl)-4,4'-bipiperidinyl-1-carbonyl)amino]-3-methylphenoxyacetic acid (31-5). 1H NMR (CDCl3): δ 1.22 (br m, 6H), 1.46 (s, 9H), 1.6 (br m, 4H), 2.2 (s, 3H), 2.6 (br t, 2H), 2.79 (t, j=11 Hz, 2H), 4.0 (br m, 5H), 4.58 (s, 2H), 6.1 (dd, j=9, 2 Hz, 1H), 6.75 (d, j=2 Hz, 1H), 7.21 (d, j=9 Hz, 1H), 8.1 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>>[C:24]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1cccnc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and nicotinic acid to yield (3aR,4S,7aR)-methyl 4-(nicotinoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=419; RT=3.553 min; HPLC Method III
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][C:19]#[N:20]>CC#N>[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[O:1][CH2:18][C:19]#[N:20])=[O:5]
Reactant: Cc1ccc(C=O)c(O)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(C=O)c(OCC#N)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.1 %

Procedure:
To a solution of 2-hydroxy-4-methylbenzaldehyde (12 g, 88 mmol) in 432 mL of CH3CN was added Cs2CO3 (34.5 g, 106 mmol) followed by 2-bromoacetonitrile (6.75 mL, 97 mmol), After the mixture was stirred at room temperature for 6 hr, the mixture was filtered through Celite to remove solid, washed with DCM, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography, 100% Heptane-20% Ethyl Acetate/80% Heptane) to give a white solid, 2-(2-formyl-5-methylphenoxy)acetonitrile (14.2 g). LCMS retention time=1.06 minutes (LC method 3); MS (m+1)=175.8. 1H NMR (400 MHz, DMSO-d6) δ 2.41 (s, 3H), 5.33 (s, 2H), 7.05 (d, J=7.8 Hz, 1H), 7.20 (s, 1H), 7.68 (s, 1H), 10.26 (d, J=0.8 Hz, 1H).
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:22][OH:23])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N([CH2:37][CH3:38])CC)C>C(Cl)Cl>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:22][OH:23])=[O:19])[NH:17][C:22](=[O:23])[CH:21]([C:38]1[CH:37]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: CCN(CC)CC
Reactant: COc1ccc([C@H](CO)NC(=O)[C@@H](N)CCCNC(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](CO)NC(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 182.2 %

Procedure:
Prepared according to the method described in Example 1(d) above from (R)-N5 -(Cbz)-(S)-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]ornithine amide hydrochloride (2.32 g, 5.13 mmol; from step (b) above), 2-nitrophenyl diphenyl acetate (1.81 g; 5.65 mmol; see Example 1(c) above), triethylamine (0.78 g, 7.70 mmol) and CH2Cl2 (150 mL), 60 hours reaction time. The reaction mixture was submitted to aqueous work up, dried, filtered and concentrated to give the crude product as an off-white solid (3.39 g). The crude product was chromatographed on silica gel eluting with CH2C2 :MeOH (98:2). Concentration of the appropriate fractions gave pure sub-title compound as a white solid (2.85 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:30])[C:26]=1[CH:27]([OH:29])[CH3:28].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([F:30])[C:26]=2[CH:27]([OH:29])[CH3:28])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C#N
Reactant: CC(O)c1c(F)cncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-c2cncc(F)c2C(C)O)ccc1C#N
Temperature: 100 °C
Yield: 52.2 %

Procedure:
To the solution of 2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (259 mg, 1.00 mmol), 1-(3-Bromo-5-Fluoro-pyridin-4-yl)-ethanol (220 mg, 1.00 mmol) and PdCl2(dpPf). CH2Cl2 adduct (65 mg, 0.08 mmol) in DMF (4 mL) was added 2M Na2CO3 solution (1.50 ml, 3.00 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and sat. NH4Cl solution. After extraction with DCM and separation, the combined extracts were concentrated and purified by ISCO 12 g (0-30% EtOAc/Heptane, v/v) to give 2-Methoxy-4-[5-fluoro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-benzonitrile (142 mg, 52%) as a white solid; ESI-MS m/z: 273 [M+1]+, Retention time 1.09 min. 1H-NMR (CDCl3, 400 MHz) δ 1.61 (d, J=6.8 Hz, 3H), 3.96 (s, 3H), 4.83 (q, J=6.8 Hz, 1H), 6.93 (d, J=1.2 Hz, 1H), 6.95 (dd, J=8.0, 1.2 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 8.29 (s, 1H), 8.51 (d, J=2.8 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[N+:35]([C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@@H:50]([NH2:52])[CH3:51])[C:41]([O:43][CH3:44])=[O:42])([O-:37])=[O:36].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[N+:35]([C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@@H:50]([NH:52][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:51])[C:41]([O:43][CH3:44])=[O:42])([O-:37])=[O:36]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@H](C)N)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.8 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (591 mg, 1.23 mmol), methyl (S)-3-nitro-4-(2-amino-1-propoxy)benzoate (313 mg, 1.23 mmol), and Et3N (257 mL, 1.84 mmol) in DMF (5 mL) was stirred at room temp for 2 days. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 310 mg (46%) methyl (S)-3-nitro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a gum. 1H-NMR (CDCl3) δ1.28 (d, 3H, J=6.8 Hz), 2.31 (s, 3 H), 3.49 (s, 2 H, 3.71 (s, 3 H), 3.92 (s, 3 H), 4.14-4.16 (m, 2 H), 4.38-4.41 (m, 1 H), 5.88-5.90 (m, 1 H), 6.49 (s, 1 H), 6.70-6.71 (m, 1 H), 6.77-6.79 (m, 1 H), 7.05-7.30 (m, 4 H), 7.55-7.57 (m, 1 H), 8.02-8.06 (m, 2 H), 8.16-8.19 (m, 1 H), 8.51-8.52 (m, 1 H); MS (FAB) m/z 551 (M++1).
Reaction SMILES: C1COCC1.[H-].[Na+].[CH3:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:27])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1)[CH:12]=O.[CH3:28][CH2:29][O:30][C:31]([CH3:33])=[O:32]>O>[CH3:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:33]/[C:31]([O:30][CH2:29][CH3:28])=[O:32])[CH:14]=[C:15]([CH3:27])[C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1
Reactant: Cc1cc(C=O)cc(C)c1Oc1ccc([N+](=O)[O-])cn1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cc(C)c(Oc2ccc([N+](=O)[O-])cn2)c(C)c1
Reaction time: 1 h

Procedure:
To a THF (100 mL) solution of triethyl phosphonoacetate (44.0 mL) was slowly added NaH (60% dispersion in mineral oil, 8.8 g) at 0° C. After stirring for 1 hour, a THF (200 mL) solution of 3,5-dimethyl-4-[(5-nitropyridin-2-yl)oxy]benzaldehyde (54.5 g) was added to the reaction mixture. After stirring at room temperature for 2 hours, AcOEt and H2O were added to the reaction mixture. The resulting precipitate was collected to give ethyl (E)-3-{3,5-dimethyl-4-[(5-nitropyridin-2-yl)oxy]phenyl}prop-2-enoate as a white powder (40.9 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:20])([CH3:19])[C@H:3]1[OH:21].[CH:22]([C:24]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[C:25]=1[C:26](OC)=[O:27])=O.C([BH3-])#N.[Na+]>[Cl-].[Zn+2].[Cl-]>[CH3:20][C:4]1([CH3:19])[C@@H:3]([OH:21])[C@H:2]([N:1]2[CH2:22][C:24]3[C:25](=[C:30]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:32][CH:33]=3)[C:26]2=[O:27])[C:7]2[CH:8]=[C:9]([S:12]([C:15]([F:17])([F:18])[F:16])(=[O:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: COC(=O)c1c(C=O)cccc1[N+](=O)[O-]
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3cccc([N+](=O)[O-])c3C2=O)[C@@H]1O
Yield: 80.2 %

Procedure:
Following the procedure and working up described in Example 10, but using 0.326 g of trans-4-amino-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran-3-ol (prepared from its hydrochloride, in turn prepared as described in Preparation 9), 0.224 g of methyl 2-formyl-6-nitrobenzoate, 0.164 g of zinc chloride and 0.075 g of sodium cyanoborohydride, 0.391 g of the title compound, melting at 283°-284° C., were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:70])[NH:10][C@H:11]([C:37](=[O:69])[N:38]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:57][CH:56]=1)[CH2:39][C:40](=[O:53])[NH:41][CH2:42][C:43]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44]1)[CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:70])[NH:10][C@H:11]([C:37](=[O:69])[N:38]([CH2:54][C:55]1[CH:56]=[CH:57][C:58]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:59][CH:60]=1)[CH2:39][C:40](=[O:53])[NH:41][CH2:42][C:43]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:46][CH2:45][CH2:44]1)[CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)NCC1(c2ccccc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)NCC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of the trityl compound from Step 4 above (0.49 g) in DCM (10 mL) was added TFA (10 mL). The solution was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in DCM and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM (2×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. Flash chromatography (10% MeOH in DCM) gave 0.22 g (50% yield over two steps) of the title compound as a white foam.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[N:9]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14](OC)=[O:15].Cl>C1COCC1.O>[C:1]([CH2:2][C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:9]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])#[N:3]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)CC#N
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
To a solution of acetonitrile (1.5 mL, 29 mmol) in THF (60 mL) was added n-butyl lithium (2.5 M solution in hexane, 10.8 mL, 29 mmol) at −78° C. The solution was stirred at about −78° C. for about 10 min and a solution of 1-tert-butyl 2-methyl (2S)-pyrrolidine-1,2-dicarboxylate (5.64 g, 25 mmol, US2007197506) in 15 mL of THF was added. The mixture was stirred at about −78° C. for about 1 hr and was subsequently allowed to reach rt (overnight). Water was added and the mixture acidified to pH 3 with 1N aqueous hydrochloric acid. The layers were separated and the organic layer was washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give tert-butyl (2S)-2-(2-cyanoacetyl)pyrrolidine-1-carboxylate (5.8 g, 24.3 mmol, 97%) as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[C:13]([O:15][CH3:16])=[O:14])[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[O:21]=[S:22]1(=[O:38])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:24](=[O:32])[N:23]1[CH2:33][CH2:34][CH2:35][CH2:36]Br>C(Cl)Cl>[O:38]=[S:22]1(=[O:21])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:24](=[O:32])[N:23]1[CH2:33][CH2:34][CH2:35][CH2:36][N:10]1[CH2:11][CH2:12][C@@H:7]([N:6]2[C:5]3[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=3[NH:3][C:2]2=[O:1])[C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1
Reactant: COC(=O)[C@@H]1CNCC[C@H]1n1c(=O)[nH]c2ccccc21
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(CCCCN2C(=O)c3cc(Cl)ccc3S2(=O)=O)CC[C@H]1n1c(=O)[nH]c2ccccc21

Procedure:
From (±)cis/trans-4-(2-oxo-1-benzimidazolinyl)-3-methoxycarbonyl-piperidine and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (prepared as shown in Example 22) using the procedures described in Example 1, Step 3, there was obtained a white solid from methylene chloride, melting point 170-176° C. Analysis calculated for C25H27ClN4O6S: C, 54.89; H, 4.98; N, 10.24; found: C, 54.65; H, 4.98; N, 10.22. The NMR was consistent with the structure.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[ClH:17]>>[ClH:17].[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:16])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: COC(=O)c1ccc(N2CCNCC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(N2CCNCC2)cc1
Temperature: 2 °C

Procedure:
4-piperazin-1-yl-benzoic acid methyl ester (17 mmol) is dissolved in 6N HCl (25 ml) and heated under reflux for 3 hours. The mixture is cooled in an ice bath to 0-4° C. and the solid material formed is filtered off, washed with acetone and dried (vacuum). A white powder with mp. >240° C. is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([CH:10]2[C:14](=[O:15])[NH:13][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]2[C:22]([O:24]CC)=[O:23])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:24][C:22](=[O:23])[C:11]3[C:10]=2[C:14](=[O:15])[NH:13][C:12]=3[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:28]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)NC(=O)C1C(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: O=C1NC(c2ccccc2)=C2C(=O)OC(c3ccc([N+](=O)[O-])cc3)=C12
Temperature: 270 °C
Yield: 76.4 %

Procedure:
The p-nitrobenzoylpyrrolinone ester 11 (300 mg, 0.90 mmol) was irradiated with microwave radiation without solvent, heating to 270° C. for 15 minutes. The crude product was then allowed to cool, methanol was added and the solid filtered off and washed with methanol. This gave the furopyrrole 12 as a red solid (230 mg, 87%).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[C:22]([Cl:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=4[CH3:28])=[C:11]3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>>[Cl:24][C:22]1[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]([CH3:28])=[C:18]([CH:23]=1)[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[CH:10][C:11]=12
Reactant: COc1ccc(Cn2ncc3c(Oc4cc(Cl)c([N+](=O)[O-])cc4C)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1Oc1ccnc2[nH]ncc12
Reaction time: 0.33 h

Procedure:
1-(4-Methoxybenzyl)-4-(5-chloro-2-methyl-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (42 g, 98.9 mmol) and 2,2,2-trifluoroacetic acid (76.2 ml, 989 mmol) were stirred at reflux for 4 h. The reaction was concentrated in vacuo, using toluene to azeotrope. The residue was diluted with EtOAc and saturated NaHCO3 was added to neutralize the acid, and the resulting suspension was stirred for 20 minutes. The precipitate was filtered and washed with water to remove residual NaHCO3. The solid was further dried by toluene azeotrope. The tan solid was left under high vacuum for 18 hours. The product (22 g, 70%) was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[C:14]=1[O:15][CH3:16].Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][N:10]([CH2:18][CH2:19][CH2:20][Cl:21])[C:9](=[O:13])[CH2:8][C:7]=2[C:14]=1[O:15][CH3:16]
Reactant: COc1ccc2c(c1OC)CC(=O)NC=C2
Reactant: ClCCCBr
Product: COc1ccc2c(c1OC)CC(=O)N(CCCCl)C=C2

Procedure:
This compound was prepared analogous to Example 1(a) by reacting 8,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (m.p.: 165°-168° C.) with 1-bromo-3-chloro-propane.