Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[NH2:16][C@H:17]([CH3:20])[CH2:18][OH:19].C(N(CC)CC)C.CO>>[OH:19][CH2:18][C@H:17]([N:16]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]=2[N+:13]([O-:15])=[O:14])[C:8]1=[O:12])[CH3:20]
Reactant: Cc1ccc2c(=O)occc2c1[N+](=O)[O-]
Reactant: C[C@@H](N)CO
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A round bottom flask was charged with 6-methyl-5-nitro-1H-isochromen-1-one (260.00 mg, 0.0012673 mol), (2R)-2-aminopropan-1-ol (143 mg, 0.00190 mol), triethylamine (1.6 L, 0.011 mol) and methanol (5 mL, 0.1 mol) and the reaction was heated at 80° C. overnight. The solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the product as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:27])[CH2:17][C:18]([O:20][CH:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])=[O:19].[NH2:28]/[C:29](/[CH3:33])=[CH:30]\[C:31]#[N:32].C(O)(=O)C>CC(O)C>[C:31]([C:30]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]([C:18]([O:20][CH:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])=[O:19])=[C:16]([CH3:27])[NH:28][C:29]=1[CH3:33])#[N:32]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(=O)CC(=O)OC(C)C(F)(F)F
Reactant: C/C(N)=C/C#N
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)OC(C)C(F)(F)F)=C(C)N1

Procedure:
60 mg (0.31 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 63 mg (0.32 mmol) of 2,2,2-trifluoro-1-methylethyl 3-oxobutanoate, 26 mg (0.32 mmol) of 3-amino-crotononitrile and 18 μl (0.32 mmol) of acetic acid in 2 ml of 2-propanol and heated under reflux under argon for 4 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 89 mg (64% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>C(O)(C)C>[ClH:1].[NH2:22][C:18]1[CH:17]=[C:16]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cccc(N)c1
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cccc(N)c3)c2cc1OC
Product: Cl
Temperature: 20 °C
Yield: 93.9 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (5.01 g, 22.3 mmol) was added in portions, over 1.5 hours, to m-phenylenediamine (2.66 g, 24.6 mmol) in refluxing isopropanol (100 mL) under an atmosphere of dry nitrogen. After the addition was complete the mixture was heated at reflux for 4 hours. The mixture was cooled to 20° C., and the precipitate was filtered, washed with chilled isopropanol and dried in vacuo to afford 6.97 g (93%) of (3-aminophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine hydrochloride (LC-MS: 297 (MH+). To a solution of the above product (50 mg, 0.169 mmol) in 80% acetic acid/H2O (2 mL), at 0° C., was added a solution of NaNO2 (18.4 mg, 0.186 mmol) in H2O (100 μL). After stirring 10 minutes at 0° C. a solution of NaN3 (12 mg, 0.185 mmol) in H2O (100 μL) was added. The mixture was allowed to warm to 20° C. and stirred for 1.5 hours. The reaction mixture was lyophilized and the residue partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic phase was wahsed further with brine, dried over Na2SO4, filtered, and concentrated, in vacuo. Recrystallization from CHCl3 /hexanes afforded 36 mg of the title product as a white solid; mp 110°-113° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>C1(C)C=CC=CC=1>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in toluene were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at 80-85° for 2-8 hours. The resultant Sunitinib base was triturated in toluene at 80-85° for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([CH3:12])[C:5]=2[N:6]=1.N([O-])=O.[Na+].[Na+].[Cl-:18]>OP(O)(O)=O.O>[Cl:18][C:2]1[S:3][C:4]2[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([CH3:12])[C:5]=2[N:6]=1
Reactant: [Cl-]
Reactant: Cc1ccc(Cl)c2sc(N)nc12
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Cl)c2sc(Cl)nc12
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a slurry of 2-amino-4-methyl-7-chlorobenzothiazole (77.2) (6.37 g) in H3PO4 (85%, 213 ml) in a 500 ml 3-necked flask with mechanical stirring and an internal temperature of <−10° C., was added dropwise a solution of NaNO2 (6.87 g) in water (11 ml). The mixture was warmed to 0° for 30 minutes and then recooled. The slurry was then slowly added to a cold (˜−5° C.) solution of CuSO4.5H2O (32 g) and NaCl (40 g) in water (128 ml) with vigorous mechanical stirring. After the foaming subsides and warming to RT, the solids were collected by filtration and rinsed with water. The solids were dissolved in ether leaving some insoluble residue. The ether solution was washed with water, and sodium bicarbonate solution. After the organic layer was concentrated, the residue was purified by flash chromatography with 10% methylene chloride in hexane to afford 2-chloro-4-methyl-7-chlorobenzothiazole (77.3) (4.48 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7](C(OC)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17]C)=O.[CH:19]([NH2:21])=[O:20].C[N:23](C)C=O.C[O-].[Na+]>CO>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:19]([NH2:21])=[O:20])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([NH2:23])=[O:17]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Reactant: NC=O
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc2cc(C(N)=O)ccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2,6-Naphthalenedicarboxamide (CAS #46711-49-3) was prepared as follows. To a two liter three neck round-bottom flask fitted with a mechanical stirrer, addition funnel and condenser/Dean Stark apparatus, with a nitrogen inlet was charged 85.4 grams (0.35 mol) dimethyl 2,6-naphthalenedicarboxylate, 105.3 grams (2.34 mol) formamide, and 200 mls of anhydrous N,N-dimethylformamide. The flask contents were heated to 100 degrees C. under a nitrogen atmosphere and held for one hour. One hundred ml of a 25 wt. % solution of sodium methoxide in methanol was added through the addition funnel in four approximately equal portions. The flask contents were then heated for four hours at 100 degrees C. during which time methanol was being condensed and removed. The flask was cooled to room temperature and one liter of isopropyl alcohol was added in two 500 ml increments. After the resulting mixture was stirred for 15 minutes it was allowed to settle for one hour. Crystallized solid material was collected by filtration and air dried in the filter for 2 hours. The recovered off-white colored product weighed 112.7 grams. The solid was washed three times in deionized water and twice in methanol which yielded 71.4 grams of greater than 98% pure product. Melting point: 347-349 degrees C.; 1H NMR: This compound is insoluble in all common NMR solvents and only sparingly soluble in DMSO-d6. (DMSO-d6) δ 8.53 ppm (broad s), 8.21 ppm (broad s), 8.07 ppm (complex multi. from 8.09−8.00 ppm), 7.55 ppm (broad s), also 3.38 ppm (water), and 2.51 (DMSO); MS m/z 214 [M].
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C([N:27](CC)CC)C>C(Cl)(Cl)Cl>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([NH:27][S:8]([C:3]3[N:4]=[CH:5][N:6]([CH3:7])[C:2]=3[Cl:1])(=[O:10])=[O:9])[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CCN(CC)CC
Reactant: Cn1cnc(S(=O)(=O)Cl)c1Cl
Solvent: ClC(Cl)Cl
Product: Cn1cnc(S(=O)(=O)NN2CCN(c3ccc(O)cc3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 20 g (93 mmol) of 5-chloro-1-methyl-4-imidazolesulfonyl chloride in 250 ml of chloroform is added dropwise at room temperature to 16 g (90 mmol) of 4-(4-hydroxyphenyl)piperazine in 250 ml of chloroform. 41 ml (0.3 mol) of triethylamine are then slowly added dropwise. When, after stirring for 6 hours at room temperature, acid chloride is no longer present by thin layer chromatography, the precipitate formed is filtered off, washed several times with water, dried and recrystallized from acetonitrile. The title compound melts at 249°-250° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([OH:19])[CH2:16][C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([O:19][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:16][C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(O)CC#N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(CC#N)OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 4-(2-cyano-1-hydroxyethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (4.24 g, 15.8 mmol) and pyridine (3.07 mL, 39.5 mmol) dissolved in dichloromethane (45 mL) at 0° C. is added methanesulfonyl chloride (3.45 mL, 42.6 mmol). After 1 hour, the reaction is not complete and is warmed to room temperature. After 18 hours at room temperature 1 equivalent of pyridine and 1 equivalent of methanesulfonyl chloride is added and stirred for 4 hours. The reaction mixture is diluted with EtOAc and washed several times with saturated NaHCO3. The organic layer is dried over Na2SO4, filtered and concentrated to give crude 4-(2-cyano-1-methanesulfonyloxy-ethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester. Assuming 100% yield, 4-(2-cyano-1-methanesulfonyloxyethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (5.47 g, 15.8 mmol) and triethylamine (11.0 mL, 79 mmol) are dissolved in MeOH (60 mL) and heated at 70° C. for 1 hour and concentrated. The residue is dissolved in EtOAc and washed with water, then concentrated and chromatographed using 100% dichloromethane to give cis/trans-4-(2-cyanovinyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (3.93 g, 99% yield) as a clear oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: OCCCCCCCCCl
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCCCCCOc1ccc2ccccc2c1
Reaction time: 168 h

Procedure:
A mixture of 2-naphthol (28.8 g), 8-chloro-1-octanol (32.8 g), potassium carbonate (40 g) and dimethylformamide (200 ml) was stirred at 60°-65° for 7 days. Water and ether were then added. The a solution was washed with aqueous potassium hydroxide, dried and evaporated. The residue was chromatographed on silica gel, eluting with 95:5 dichloromethane:methanol, and the product so obtained was crystallized from hexane, to give the title compound, mp 67°-9°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([NH:36][C:37]1[CH:46]=[CH:45][C:40]([O:41][CH2:42][CH2:43]Cl)=[CH:39][CH:38]=1)(=[O:35])[CH3:34]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][N:25]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:43][CH2:42][O:41][C:40]2[CH:45]=[CH:46][C:37]([NH:36][C:33](=[O:35])[CH3:34])=[CH:38][CH:39]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(OCCCl)cc1
Reactant: c1ccc(CNCCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCCN(CCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)Cc2ccccc2)cc1

Procedure:
A mixture of N-2-(3,4-dibenzyloxyphenyl)ethyl benzylamine (12.0 g.), 2-(4-acetamidophenoxy)ethyl chloride (3.1 g.) and dry dimethylformamide (10 ml.) was boiled under reflux for 10 hours. The solution was cooled, more dimethylformamide (15 ml.) added, and the precipitated solid removed by filtration. The filtrate was evaporated in vacuo to dryness and the resultant solid stirred in chloroform, after which undissolved material was removed by filtration and the filtrate was evaporated in vacuo to dryness to give the crude product, N-[2-(3,4-dibenzyloxyphenyl)ethyl]-N-[2-(4-acetamidophenoxy) ethyl]benzylamine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[NH2:22][C@@H:23]1[CH2:27][C:26](=[O:28])[N:25]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]1=[O:37].CCN(CC)CC.S(Cl)(Cl)(=O)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:30]([O:29][N:25]1[C:26](=[O:28])[CH2:27][C@@H:23]([NH:22][S:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][CH:5]=3)[CH2:10][CH2:11]2)(=[O:17])=[O:16])[C:24]1=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: N[C@@H]1CC(=O)N(OCc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=S(=O)(Cl)Cl
Product: O=C1C[C@@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1OCc1ccccc1
Temperature: 25 °C

Procedure:
4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl chloride (164 mg; 0.50 mmol), (3R)-3-Amino-1-benzyloxy-pyrrolidine-2,5-dione hydrochloric acid (102 mg; 0.40 mmol), Et3N (180 ul; 1.30 mmol) and DMAP (25 mg; 0.20 mmol) was dissolved in DMF (1 ml). The mixture was heated in a microwave oven at 200 W for 10 seconds and allowed to cool to room temperature. Another portion of the sulfonyl chloride (164 mg; 0.50 mmol) and Et3N (180 ul; 1.30 mmol) in DMF (1 ml) was added followed by heating for 10 seconds at 200 W. Reaction mixture were evaporated and filtered through Si-60 gel with EtOAC:Heptane as eluent. This crude product was purified on a C-18 column with an HPLC system using a gradient: 70% (H2O+0.1% TFA):30% (MeCN+0.1% TFA) to 100% (MeCN+0.1% TFA), gradient time=35 min, flow=10 ml/min, UV=220 nm. Fractions containing the product was evaporated to a small volume, the water phase was neutralised with 5% NaHCO3 and the product was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and evaporated to give the title compound as a colourless solid. Obtained 94 mg (45%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]2[C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][C:15]=3[CH2:14][CH2:13]2)[N:22]=[C:21]([CH3:25])[N:20]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:19]4=[O:34])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46].ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]2[C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][C:15]=3[CH2:14][CH2:13]2)[N:22]=[C:21]([CH3:25])[N:20]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:32])[CH3:31])[C:19]4=[O:34])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:41]1[C:40]([F:43])=[C:39]([F:44])[C:38]([F:45])=[C:37]([F:46])[C:36]=1[F:35])=[O:5]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)O)c(F)c1)CC3
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1)CC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-benzoic acid (0.75 g), pentafluorophenol (1.77 g), N,N-dicyclohexylcarbodiimide (0.66 g), N-hydroxybenzotriazole (0.01 g) and methylene chloride (100 ml) was stirred at ambient temperature for 18 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluant. There was thus obtained pentafluorophenyl o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoate as a gum (0.72 g);
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=[CH:11][CH:10]=2)([O-])=O>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:3][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Temperature: 5 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
Nickel(II) chloride hexahydrate (18.4 g) was dissolved in MeOH (360 mL) and cooled to 5° C. Sodium borohydride (2.9 g) was added followed by the product from step (i) (28 g). More sodium borohydride (11.7 g) was added slowly keeping the temperature below 23° C. then stirred for 1 h. The reaction mixture was filtered through celite and the filtrate was poured into sodium bicarbonate solution (300 mL). The solvent was reduced by half and then extracted with chloroform, combined organics were dried, and solvent removed to give the subtitle compound as a solid (22 g); MS multimode (+) 331
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][C:25]([C:31]#[N:32])=[CH:26][CH:27]=4)[CH:22]=3)[S:16]([NH2:19])(=[O:18])=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[ClH:40].[NH2:41][OH:42]>C(O)C>[Cl-:40].[Cl-:40].[Cl-:40].[OH:42][NH:41][C:31]([C:25]1[CH:24]=[C:23]2[C:28]([CH:29]=[CH:30][C:21]([CH2:20][N:15]([C:12]3[CH:11]=[CH:10][C:9]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:14][CH:13]=3)[S:16]([NH2:19])(=[O:18])=[O:17])=[CH:22]2)=[CH:27][CH:26]=1)=[NH:32]
Reactant: CN1CCCN(c2ccc(N(Cc3ccc4ccc(C#N)cc4c3)S(N)(=O)=O)cc2)CC1
Reactant: NO
Reactant: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCCN(c2ccc(N(Cc3ccc4ccc(C(=N)NO)cc4c3)S(N)(=O)=O)cc2)CC1
Product: [Cl-]
Yield: 16.1 %

Procedure:
230 mg of N-(4-(4-methylhexahydro-1H-1,4-diazepin-1-yl)phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamide was dissolved in 9.2 ml of ethanol, to which were added 0.25 ml of triethylamine and 90 mg of hydroxylamine hydrochloride. The mixture was heated for reflux for 2 hours. The reaction mixture was evaporated, and the resulting residue was purified through silica gel column chromatography using an eluent solvent of concentrated ammonia water/methanol/chloroform (0.1/1/7). The solvent was evaporated, and a small amount of aqueous 1 N hydrochloric acid was to the residue, and then evaporated again in vacuo, to obtain 41 mg of N-[(7-hydroxyamidino-2-naphthyl)methyl]-N-[4-(4-methylhexa-hydro-1H-1,4-diazepin-1-yl)phenyl]sulfamide trichloride.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:5]([C:7]1[S:17][C:16]2[N:18]3[C:9](=[CH:10][N:11]=[C:12]3[CH:13]=[CH:14][CH:15]=2)[CH:8]=1)=[O:6].C(N(CC)CC)C.Br[CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)C>[CH3:3][N:4]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:22][CH2:21]1)[C:5]([C:7]1[S:17][C:16]2[N:18]3[C:9](=[CH:10][N:11]=[C:12]3[CH:13]=[CH:14][CH:15]=2)[CH:8]=1)=[O:6]
Reactant: BrCCCc1ccccc1
Reactant: CN(CC1CCNCC1)C(=O)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(CC1CCN(CCCc2ccccc2)CC1)C(=O)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 464.3 mg (1.16 mM) of N-methyl-N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 0.8 ml (5.74 mM) of triethylamine in ethanol was added 0.21 ml (1.38 mM) of l-bromo-3-phenylpropane at room temperature, and the mixture was refluxed under nitrogen for 15 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 20-50%) to provide the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[N:8]1[C:13]2[NH:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](=[O:19])[NH:18][C:12]=2[CH:11]=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:14]1[C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](=[O:19])[NH:18][C:12]2[CH:11]=[CH:10][CH:9]=[N:8][C:13]1=2)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: Cc1ccccc1C
Product: O=C1Nc2cccnc2N(C(=O)CCCCl)c2ccccc21

Procedure:
A solution of 4-chlorobutyryl chloride and 5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one in xylene was reacted to obtain 11-(4-chlorobutyryl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which after crystallization from ethyl acetate melted at 205°-207° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1.C(=O)(O)[O-].[Na+].C1COCC1.F[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31]>O>[N+:30]([C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=1[N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1)([O-:32])=[O:31]
Reactant: O[C@@H]1CCCNC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCC[C@@H](O)C1
Reaction time: 14 h

Procedure:
To a 100-mL round bottom flask (RBF) was added (R)-piperidin-3-ol hydrochloride (1.29 g, 9.37 mmol), sodium bicarbonate (2.76 g, 32.8 mmol), THF and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.31 ml, 9.37 mmol). The yellow mixture was heated to 75° C. with a water-cooled reflux condensor and allowed to stir 14 h. The reaction was filtered through a glass frit, rinsing with EtOAc, and concentrated in vacuo to give (R)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol as an orange oil.
Reaction SMILES: [I-:1].[CH2:2]([C:4]1[SH+:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:3].C([I:15])C>C(O)C>[IH:15].[I-:1].[CH2:2]([C:4]1[SH+:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:3]
Reactant: CCI
Agent: CCc1ccccccc[sH+]1
Agent: [I-]
Solvent: CCO
Product: I
Temperature: 25 °C

Procedure:
Ethyl-thioninium iodide (2.00 g, 4.28 mmol) was dissolved in ethanol (100 cm3) and ethyl iodide (27.35 g, 175 mmol) was added while stirring. The mixture was heated at reflux for 18 hours, then cooled to room temperature, giving a precipitate that was filtered and washed with ethanol to yield the title compound (1.02 g, 40%) as a bronze solid. δH (250 MHz; D2O): 7.90 (2H, br d, ArH), 7.42 (4H, s, ArH), 2.45 (8H, br q, NCH2), 1.23 (12H, br t, CH3).