Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:48])[C@@H:32]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:33][S:34][S:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:48])[C@@H:32]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:33][S:34][S:35][C:36]([CH3:38])([CH3:39])[CH3:37])[C:23]([O:25][CH2:2][C:1]#[N:4])=[O:24])=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Reaction time: 5 h
Yield: 78 %

Procedure:
N,N-diisopropylethylamine (0.073 mL, 0.421 mmol) and subsequently bromoacetonitrile (0.080 mL, 1.15 mmol) were added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoic acid (Compound 52) (206 mg, 0.383 mmol) in acetonitrile (0.3 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 5 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Compound 53) (172.2 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH2:11]C)[N+:3]=1[O-]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: CCc1cc([N+](=O)[O-])cc(Br)[n+]1[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1cc(N)cc(Br)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromo-6-ethyl-4-nitro-pyridine 1-oxide (15.9 g, 69 mmol) in acetic acid (310 ml) was treated with powdered iron (25.8 g, 462 mmol). The mixture was slowly heated to 100° C. and kept for 1 hr. Then the reaction mixture was cooled to rt and filtered. After evaporation of the solvent the residue was crystallized to yield the title compound as a beige material (88%). Mp. 75-77° C. (pentane), MS: m/e=200 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:30][CH:29]=2)[N:3]=1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-methanesulfonylbenzylamine hydrochloride and DBU in DME. ES-MS m/e (%): 370 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:27])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[Si:28]([O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Si:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:10]([CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:27])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:21][CH:22]=2)=[CH:40][CH:41]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a suspension of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (710 mg), 4-[[tert-butyl(dimethyl)silyl]oxy]phenylboronic acid (457 mg), triethylamine (1.26 ml) and powdered 4 Å molecular sieves (700 mg) in dichloromethane (18 ml) was added copper(II) acetate (330 mg), and the mixture was stirred at room temperature for 18 hours under ambient atmosphere. The resulting slurry was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give tert-butyl [2-[4-[4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy]phenyl]ethyl][(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (600 mg).
Reaction SMILES: [Na].[CH3:2][C:3]([SH:6])([CH3:5])[CH3:4].[H-].[Na+].ClC(C)[C:11]([C:13]1[CH:14]=C(CC(O)=O)C(OC)=C[CH:18]=1)=O>C1COCC1.O>[C:3]([S:6][C:13]([CH3:14])([CH3:18])[CH3:11])([CH3:5])([CH3:4])[CH3:2]
Reactant: CC(C)(C)S
Reactant: COc1ccc(C(=O)C(C)Cl)cc1CC(=O)O
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)SC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a 50 mL round bottom flask containing 0.9 grams (8.82 mmole) of the sodium salt of 2-methyl-2-propanethiol was added 0.25 grams of sodium hydride (11.3 mmole) and the resulting mixture placed under vacuum and then under a nitrogen atmosphere. To the mixture was then added 15 mL of anhydrous tetrahydrofuran and the mixture cooled to 0° C. To the cooled mixture was added 1.5 grams (5.84 mmole) of 9 dissolved in 15 mL of anhydrous THF over a period of 10 minutes. After addition, the reaction mixture was allowed to stir, at room temperature and under a nitrogen atmosphere for 18 hours. After 18 hours the volatile components of the reaction mixture were removed under reduced pressure to give a brown solid. The brown solid was dissolved in 80 mL of H2O and aqueous washed with 100 mL of diethyl ether. The aqueous layer was then acidified with 1 mL of concentrated HCl (pH=1) and then extracted (2×100 mL) with diethyl ether and organic layers combined, dried over MgSO4, filtered and volatile components removed under reduced pressure to give 1.75 grams of the t-butyl thioether product which was used without any further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][C:5](Br)=[CH:4][C:3]=1[S:14]([O-:17])(=[O:16])=[O:15].[Na+:18].[OH-].[Na+].C(O)C>[Zn].CO>[NH2:1][C:2]1[C:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[S:14]([O-:17])(=[O:16])=[O:15].[Na+:18]
Reactant: Nc1c(-c2cccs2)cc(Br)cc1S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CO
Solvent: CCO
Product: Nc1c(-c2cccs2)cccc1S(=O)(=O)[O-]

Procedure:
21 g (59 mmol) of sodium 2-amino-5-bromo-3-(2-thienyl)benzenesulphonate are heated at 100° C. for 1 hour in the presence of 350 ml of 10% sodium hydroxide solution, 15 ml of ethanol and 7.4 g of zinc. The temperature of the reaction medium is allowed to return to room temperature and 300 ml of methanol are added. The mixture is filtered through Celite, the filtrate is concentrated and the residue is taken up in 1N sodium hydroxide solution at 0° C. and dried under vacuum.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[CH:10]=[CH:9]2)[CH2:4][CH2:3]1.[CH3:21][O:22][C:23]1[C:32]([CH2:33][CH:34]=O)=[C:31]2[C:26]([C:27](=[O:38])[CH2:28][C:29]([CH3:37])([CH3:36])[O:30]2)=[CH:25][CH:24]=1.O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:21][O:22][C:23]1[C:32]([CH2:33][CH2:34][N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=4)[CH:10]=[CH:9]3)[CH2:6][CH2:7]2)=[C:31]2[C:26]([C:27](=[O:38])[CH2:28][C:29]([CH3:37])([CH3:36])[O:30]2)=[CH:25][CH:24]=1
Reactant: COc1ccc2c(c1CC=O)OC(C)(C)CC2=O
Reactant: COC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
2.92 g of methyl 1-piperidin-4-yl-1H-indole-6-carboxylate hydrochloride and 2.92 g of (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde were added with 58.4 mL of tetrahydrofuran and 14.6 mL of acetic acid warmed to 40° C. and the reaction mixture was stirred for about 3 hours. The reaction mixture was cooled with an ice-water bath, and 2.52 g of sodium triacetoxyborohydride was added portionwise divided into three. The reaction mixture was warmed to room temperature and 30 minutes later, progress of the reaction was confirmed. The reaction mixture was cooled with an ice-water bath again and 87 mL of toluene and 29 mL of water were added thereto and the aqueous layer was discarded. The organic layer was washed with 49 mL, 69 mL, 30 mL of 1 N aqueous sodium hydroxide sequentially and then with 29 mL, 14 mL of 5% sodium chloride solution and 14 mL of water. The solvent was evaporated and 4.80 g of the crude title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32](O)=[O:33])=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:79][CH2:80][CH2:81][N:82]([CH2:86][CH2:87][OH:88])[CH2:83][CH2:84][OH:85]>CN(C)C=O>[OH:85][CH2:84][CH2:83][N:82]([CH2:86][CH2:87][OH:88])[CH2:81][CH2:80][NH:79][C:32]([C:5]1[C:6]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=1)=[O:33]
Reactant: NCCN(CCO)CCO
Reactant: COc1cc(-c2csc3c(C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2csc3c(C(=O)NCCN(CCO)CCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 20 mL scintillation vial was charged with 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (0.070 g, 0.148 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.067 g, 0.177 mmol), 1-hydroxybenzotriazole hydrate (0.024 g, 0.177 mmol) and N,N-dimethylformamide (1.5 mL). To the suspension was added diisopropylethylamine (0.100 mL, 0.592 mmol) and 2-[(2-aminoethyl)(2-hydroxyethyl)amino]ethanol (0.024 mg, 0.162 mmol). The vial was flushed with nitrogen gas prior to capping, and the reaction mixture was shaken at room temperature for 12 hours. Upon completion of the reaction, methylene chloride (2 mL) and saturated sodium bicarbonate solution (2 mL) were added. The solution was filtered through an Empore™ cartridge, and the solvents removed under reduced pressure. The residues were taken up in a minimal amount of methanol and eluted (gravity) through a Si-carbonate™ cartridge (2 gram, 6 mL). The organic solution obtained was concentrated and the resulting residue triturated with water to give N7–2-[di(2-hydroxyethyl)amino]ethyl-4-amino-3-(3-methoxy-4-[(1-methyl-1H-2-indolyl)carbonyl]aminophenyl)thieno[3,2-c]pyridine-7-carboxamide as a precipitate. The title compound was collected and dried by vacuum filtration (15 mg, 14%). LCMS (Conditions a) Rt 2.62 min., 603.4 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.51 (s, 1H), 8.39 (t, J=5.5 Hz, 1H), 7.99 (dd, J=7.8 Hz, 8.2 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.58 (s, 1H), 7.35 (s, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.20 (d, J=1.6 Hz, 1H), 7.15 (dd, J=7.8 Hz, 7.2 Hz, 1H), 7.07 (dd, J=8.2 Hz, 1.6 Hz, 1H), 4.41 (t, J=5.8 Hz, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.44 (q, J=5.8 Hz, 4H), 3.34 (m, 2H), 2.68 (t, J=7.2 Hz, 2H), 2.61 (t, J=5.8 Hz, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1.O=[As](O[As](=O)=O)=O.S(=O)(=O)(O)O.[NH4+].[OH-].[CH3:38][CH2:39][CH2:40]CCC>O.C(OCC)(=O)C.OCC(CO)O>[N:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]2[CH:13]=[C:14]3[C:2](=[C:3]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=4)[CH:4]=2)[N:1]=[CH:40][CH:39]=[CH:38]3)=[CH:12][CH:11]=1
Reactant: CCCCCC
Reactant: Nc1ccc(Cc2ccncc2)cc1-c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: O=[As](=O)O[As](=O)=O
Agent: [NH4+]
Solvent: O
Solvent: OCC(O)CO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2cc(Cc3ccncc3)cc3cccnc23)c1
Temperature: 100 °C

Procedure:
4-[4-Amino-3-(3-nitrophenyl)benzyl]pyridine (600 mg) was combined with glycerol (489 mg) and arsenic pentoxide (325 mg) under nitrogen. The reaction mixture was heated to 100° C. for 30 minutes. Concentrated sulfuric acid (406 mg) was added in a dropwise manner and the reaction mixture was further heated to 150° C. for 2 hours. The reaction was monitored by TLC (9:1, hexane:ethyl acetate) where an aliquot was worked up by adding the product from the reaction to H2O, basifying with NH4OH and extracting with ethyl acetate. When TLC indicated that greater than 90% of the starting material had been converted, the reaction mixture was removed from the heat, ice (approximately 1 gm) was added, and NH4OH was added to basify the mixture. A precipitate was filtered out of the mixture, washed with H2O and air dried. The resulting solid was suspended in hot ethyl acetate and filtered. The filtrate was concentrated and chromatographed by preparative thin-layer chromatography (4:1, hexane:ethyl acetate), the spot with the higher Rf value was isolated yielding 181 mg of 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline as a viscous yellow oil. The product was recrystallized from diethyl ether as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+]>OCC1CCCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]3[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: OCC1CCCCC1
Agent: [C-]#N
Agent: [K+]
Product: O=C(OCC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 16 h

Procedure:
A mixture of 6.9 g (20 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-1-carboxylate, 0.6 g (9.2 mmol) of potassium cyanide and 70 ml of hydroxymethyl-cyclohexane is stirred at 130° for 16 hours, a small amount of solvent being distilled off twice in the course of the reaction. The mixture is subsequently evaporated in a high vacuum, the residue is partitioned between water and chloroform, the chloroform solution is washed twice with saturated sodium chloride solution and dried over magnesium sulphate. After evaporation of the chloroform soluticn, the residue is crystallized from ethyl acetate/n-hexane, there being obtained cyclohexylmethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 123°-124° C.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][O:4][NH:3]1.[CH2:13]=O>C(O)=O>[CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][O:4][N:3]1[CH3:13]
Reactant: CC1NOCCc2ccccc21
Reactant: C=O
Solvent: O=CO
Product: CC1c2ccccc2CCON1C

Procedure:
To 1.1 ml. of 99 percent formic acid, 1 g. (0.0061 mole) of 1-methyl-1,2,4,5-tetrahydro-3,2-benzoxazepine and 0.45 ml. of 38 percent formaldehyde were added. After heating the reaction mixture at 60°-70° C. for about 6 hours, the excess of formic acid was distilled off. The residue was alkalinized with sodium carbonate and then extracted several times with diethyl ether. After washing with water and drying, the organic solution was evaporated. The residue was distilled at 60° C./0.1 mm Hg, giving 0.6 g. of 1,2-diemthyl-1,2,4,5-tetrahydro-3,2-benzoxazepine.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([NH2:26])[CH:22]=[CH:21]4)[CH:10]=2)=[CH:5][CH:4]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([NH:26][C:29](=[O:31])[CH3:30])[CH:22]=[CH:21]4)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1
Product: CC(=O)Nc1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1

Procedure:
This material was prepared according to the method described in Example 66 using 8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamine, (Example 2(d), Method B), (0.79 g, 2.1 mmol) and acetic anhydride (2.5 mL, 2.6 mmol). Purification by silica gel chromatography (2:1 hexanes: EtOAc) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 425 (M+1). Mp: 203.8–206.0° C. Anal. Calcd for C22H15F3N4O2: C, 62.26; H, 3.56; N, 13.20. Found: C, 62.28; H, 3.51; N, 13.15.
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].C(=O)(O)[O-]>>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 0.5 h

Procedure:
VM-2 antibody (5 mg/ml) was reacted with a tenfold molar excess of fluorescein isothiocyanate immobilized on Celite (Molecular Probes) for 30 minutes in the dark at room temperature in a 0.2M bicarbonate buffer, pH 9.2. Excess fluorescein isothiocyanate was removed by gel chromatography on a Sephadex G50 column in phosphate buffered saline. The fluorophore/protein ratio was calculated from the absorbance of the conjugate at 493 nm and 280 nm and varied between 2.4 to 4.2 from one preparation to another.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12]1.[OH-].[Na+].[NH4+].[Cl-].CC(O)=O>C1COCC1.CO.O>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1(c2c(OC)cccc2OC)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(OC)c1C1(C(=O)O)CC1
Yield: 91.4 %

Procedure:
A mixture containing the ester 18 (21.11 g, 89.4 mmol) and 10 M NaOH (36 ml, 4 equiv) in THF (220 ml), MeOH (110 ml) and water (55 ml) was stirred at reflux for 4 days. Half-saturated NH4Cl (600 ml) and AcOH (25 ml) were then added and the acid 19 was extracted into i-PrOAc. The organics were dried over Na2SO4 and concentrated. Trituration of the residue in ether:hexane 1:3 (200 ml) yielded 18.15 g (91%) of 19 as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.CCN=C=NCCCN(C)C.C1C=CC2N(O)[N:40]=[N:39]C=2C=1>O.C(N(CC)CC)C.C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:39][NH2:40])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NNC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.2 %

Procedure:
To a solution of THF (50 mL) of 4-benzyloxy-phenylacetic acid (7.0 g) were added hydrazine monohydrate (4.3 g), WSC (6.7 g), HOBt (4.7 g), and triethylamine (3.5 g), which was stirred for 15 hours at room temperature. Water was added to the reaction mixture, and the precipitated solids were filtered off to obtain the titled compound (1.2 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([CH2:11][S:12][CH2:13][CH2:14][N:15]2C(=O)C3=CC=CC=C3C2=O)[CH:8]=[CH:7][CH:6]=1)[CH3:3].O.NN>CO>[NH2:15][CH2:14][CH2:13][S:12][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[N:10]=1
Reactant: CN(C)Cc1cccc(CSCCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: CO
Product: CN(C)Cc1cccc(CSCCN)n1

Procedure:
6-Dimethylaminomethyl-2-[(2-phthalimidoethyl) thiomethyl]pyridine (24.3 g, 0.068 mol) is dissolved in methanol (150 ml) and hydrazine hydrate (4.8 g, 0.087 mol) is added. The solution is refluxed for 11/2 hours and is concentrated in vacuo. The solid residue is dissolved in water (250 ml) 12N HCl (35 ml) is added and the mixture is cooled and filtered. The filtrate is washed with chloroform and concentrated in vacuo. The residue is basified with excess sodium bicarbonate and concentrated to dryness in vacuo. The solid residue is extracted with chloroform/methanol (50/50) (200 ml) and the extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This gives 10.3 g of 2-[(2-aminoethyl)thiomethyl]-6-dimethylaminomethyl pyridine as a light amber oil.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:4]=[N:3][N:2]1[C:10]([NH:33][CH2:34][CH3:35])=[N:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].O.NN>CCO>[NH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:11]=[C:10]([N:2]2[N:3]=[CH:4][C:5]3([CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:1]2)[NH:33][CH2:34][CH3:35])(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: CCNC(=NS(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)N1CC2(C=N1)CCCC2
Agent: NN
Solvent: O
Solvent: CCO
Product: CCNC(=NS(=O)(=O)c1ccc(CN)cc1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Yield: 64.9 %

Procedure:
2.51 g N-[(2,3-Diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]-4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzenesulfonamide was taken up in 50 mL EtOH. After addition of 0.70 mL hydrazine hydrate, the mixture was refluxed for 2 h. After cooling to room temperature, the formed precipitate was filtered off. The filtrate was concentrated, and the residue was triturated with DCM. The solids were filtered off, and the filtrate was evaporated to dryness to give 1.20 g (67%) of 4-Aminomethyl-N-[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]benzenesulfonamide as a red oil. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.22 Hz, 3H), 1.59-1.83 (m, 8H), 3.46 (q, 2H), 3.82 (br.s., 2H), 3.92 (br.s., 2H), 6.82 (s, 1H), 7.40 (d, J=8.13 Hz, 2H), 7.88 (d, J=8.13 Hz, 2H) [NH2 & guanidine NH invisible].
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[NH:28][C:29](=[O:31])[CH3:30])[CH2:17][CH2:16]3)OC2=O)=CC=1>CS(C)=O>[C:29]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1)(=[O:31])[CH3:30]
Reactant: COc1ccc(N2C[C@H](CN3CCC(Oc4ccccc4NC(C)=O)CC3)OC2=O)cc1
Solvent: CS(C)=O
Product: CC(=O)Nc1ccccc1OC1CCNCC1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-o-acetamido-phenoxypiperidino)methyl]-2-oxazolidinone, m.p. 98°-102°; [α]D =-22.5° (DMSO);