Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[C:14]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cn1cc(Br)cn1
Product: CCOC(=O)c1ccc(C)c(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methyl-benzoic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: [P:1]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)([OH:4])([OH:3])=[O:2].[OH-].[Na+].[C:12]([S:15][CH:16]([CH3:20])[C:17](Cl)=[O:18])(=[O:14])[CH3:13].Cl>O>[C:12]([S:15][CH:16]([CH3:20])[C:17]([N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[P:1](=[O:4])([OH:3])[OH:2])=[O:18])(=[O:14])[CH3:13]
Reactant: CC(=O)SC(C)C(=O)Cl
Reactant: O=P(O)(O)C1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)SC(C)C(=O)N1CCCC1P(=O)(O)O

Procedure:
2-Phosphonopyrrolidine is dissolved in water and the pH of the solution adjusted to 7 by the addition of sodium hydroxide. The solution is cooled in an ice bath, and 2-(acetylthio)propanoyl chloride is added dropwise. During the addition, the pH of the solution is maintained at 7 by the addition of 2 N sodium hydroxide. After the addition is complete, the reaction mixture is acidified to pH 2 with concentrated HCl and extracted with ethyl acetate. Drying (over MgSO4) and evaporation of the extracts affords a residue of the product, [1-(2-acetylthio-1-oxopropyl)-2-pyrrolidinyl]phosphonic acid.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH2:6]O)([CH3:3])[CH3:2].O=S(Cl)[Cl:16]>C(Cl)Cl>[Cl:16][CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)N(CCO)c1ccccc1
Solvent: ClCCl
Product: CC(C)N(CCCl)c1ccccc1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
In a mixture of compound 4b (483 mg, 2.7 mmol) and CH2Cl2 (50 mL), SOCl2 (0.24 ml, 3.2 mmol) was added dropwise over 20 min. After the addition was complete, the mixture was heated to reflux for one hour. After cooling to room temperature, the mixture was quenched carefully with cold, saturated aqueous K2CO3 (100 mL). The mixture was then extracted with CH2Cl2, and the combined organic layer was washed with saturated aqueous K2CO3, washed with brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc (8/1) to provide the intermediate 4c (170 mg, 0.86 mmol, 31.8% yield) as a yellow brown oil. 1H NMR (400 MHz, CDCl3) δ 7.35-7.26 (m, 2H), 6.86-6.76 (m, 3H), 4.19-4.04 (hept, J=6.5 Hz, 1H), 3.65-3.50 (td, J=12.6, 7.3 Hz, 4H), 1.29-1.22 (d, J=6.6 Hz, 6H).
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)[CH3:3].O.[OH-].[Li+]>CO>[OH:1][CH:2]([C:4]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)[CH3:3]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)O)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(C)O)c([N+](=O)[O-])cc1OCCCC(=O)O

Procedure:
Methyl 4-[4-(1-hydroxyethyl)-2-methoxy-5-nitrophenoxy]butyrate (5.04 g) from above was stirred with lithium hydroxide monohydrate in methanol using conventional protocols. 4-[4-(1-Hydroxyethyl)-2-methoxy-5-nitrophenoxy]butyric acid was obtained as an amorphous yellow solid (4.0 g, 83%). 1H NMR (CDCl3) δ1.34 (3H, d, J=11 Hz, MeCOH), 2.03 (2H, m, CCH2C), 2.38 (2H, t, J=7.3 Hz, CH2CO), 3.81 (3H, s, OMe), 3.96 (2H, t, J=7.4 Hz, CH2O), 4.13 (2H, brs, OH), 5.38 (1H, q, J=10.8 Hz, CHOH), 7.19 (1H, s, aromatic, and 7.43 (1H, s, aromatic).
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:11]=[C:10]([S:12]([O-:15])(=O)=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].P(Cl)(Cl)([Cl:18])=O>>[N+:2]([C:5]1[CH:11]=[C:10]([S:12]([Cl:18])(=[O:15])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ccc(S(=O)(=O)[O-])cc1[N+](=O)[O-]
Agent: [Na+]
Product: Nc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
A mixure of o-nitroaniline-p-sulfonic acid sodium salt (25.00 g, 104 mmol) and phosphoryl chloride (75 mL, 804 mmol) under Argon was heated to reflux and vigorously stirred for 4 hours. After cooling to ambient temperature, the reaction mixture was carefully added to a large excess of ice. The resulting slurry was stirred for 15 min., filtered and dried under vacuum to provide o-nitroaniline-p-sulfonyl chloride (21.43 g, 87%) as a yellow solid. H1-NMR (dimethylsulfoxide-D6): 5.8 (b, 2H), 6.97 (d, 1H, J=8.8), 7.57 (m, 1H), 8.18 (d, 1H, J=2.0).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)[NH2:3].C([O-])(=O)C.[Na+].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>O.C(O)C>[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[N:3][NH:2][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1
Reactant: C1=COCCC1
Reactant: CS(=O)(=O)NCc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)NCc1ccc(NN=CCCCCO)cc1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a solution of 23.9 g of crude N-[(4-hydrazinylphenyl)methyl]methanesulfonamide hydrochloride in 175 mL of water and 300 mL of ethanol was added sufficient sodium acetate to bring the pH to 4. To the resulting suspension was added 10.4 mL (114 mmol, 1.3 equiv.) of 3,4- dihydro-2H-pyran. The mixture was then stirred for twenty hours at room temperature. The ethanol was removed in vacuo. The pH was raised to 10 by adding solid potassium carbonate and the mixture was extracted three times with 50 mL portions of methylene chloride. The combined organic layers were washed with 25 mL of saturated aqueous sodium chloride, dried over magnesium sulfate and filtered to give an oil. The oil was purified by chromatography on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide to yield 11.1 g (39%, two steps) of pure N-[[4-[2-(5-hydroxypentylidene)hydrazinyl]phenyl]methyl]methanesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1.C1C(=O)N([Br:41])C(=O)C1>>[Br:41][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1
Yield: 28.3 %

Procedure:
Following General Procedure I, (R)-tert-butyl 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (220 mg, 0.39 mmol) was reacted with NBS (90 mg, 0.51 mmol) to afford the desired product (60 mg, 28%) as a reddish oil: ESI MS m/z 543 [C26H27BrN2O4S+H]+.
Reaction SMILES: ClC(OC(Cl)C)=O.[CH3:8][C:9]12[CH2:23][CH:18]([N:19](C)[CH2:20][CH2:21]1)[CH2:17][CH2:16][C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1.C([O-])(O)=O.[Na+].ClCCl>ClCCCl>[CH3:8][C:9]12[CH2:23][CH:18]([NH:19][CH2:20][CH2:21]1)[CH2:17][CH2:16][C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCC2(C)CC1CCc1ccccc12
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC12CCNC(CCc3ccccc31)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Chloroethyl chloroformate (3.8 mL) is added dropwise to a mixture of 1,11-dimethyl-11-aza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-triene (0.75 g) and NaHCO3 (2.9 g) in 1,2-dichloroethane (3.5 mL) chilled in an ice bath. The reaction mixture is warmed to room temperature in the cooling bath and stirred overnight. Then, dichloromethane (20 mL) is added and the precipitate is removed by filtration. The filtrate is concentrated under reduced pressure and the residue is dissolved in methanol (20 mL). The resulting solution is stirred at reflux for 2 h. The solution is concentrated and the residue is purified by HPLC (water/MeCN/NH3) to give the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.C(Cl)(=O)C([Cl:17])=O>C1(C)C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([Cl:17])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCc2ccccc2C1
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCc2ccccc2C1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
The suspension of 1,2,3,4-tetrahydro-2-naphthoic acid (500 mg, 2.84 mmol) in 5 ml of toluene was treated with oxalyl chloride (720 mg, 5.675 mmol). The mixture was stirred at 50° C. for 5 hrs. All volatile materials were removed in vacuo and product 1,2,3,4-Tetrahydro-2-naphthoyl chloride was obtained as a colorless oil, which was used for next step reaction without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[CH2:17][CH2:16][O:15][C:14]4[CH:18]=[C:19]([C:22]([OH:24])=O)[CH:20]=[N:21][C:13]=4[N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:27](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[CH2:17][CH2:16][O:15][C:14]4[CH:18]=[C:19]([C:22]([NH2:27])=[O:24])[CH:20]=[N:21][C:13]=4[N:12]3[CH:25]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1nccc1-c1cn2c(n1)CCOc1cc(C(=O)O)cnc1-2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1nccc1-c1cn2c(n1)CCOc1cc(C(N)=O)cnc1-2
Reaction time: 0.17 h

Procedure:
A mixture of 17 mg (0.05 mmol) of 9-(1-isopropyl-1H-pyrazol-5-yl)-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylic acid, 30 mg, (0.061 mmol) of HATU and 0.022 ml (0.155 mmol) of triethylamine in 2 ml of DMF was stirred for 10 min. Ammonia (gas) was bubbled through the mixture for 5 min. The mixture was stirred for 1 hour, concentrated in vacuum and partitioned between ethyl acetate and 0.01 N aqueous HCl. The organic layer was concentrated and the residue purified on 4 g silica column eluting with 7-8% Methanol in DCM to give 114. Yield 2.4 mg. MS(ESI+) 339.2. 1H NMR (400 MHz, CH3OH+D2O) δ 8.70 (d, J=1.8, 1H), 8.33 (s, 1H), 8.05 (d, J=1.8, 1H), 7.52 (s, 1H), 6.48 (d, J=1.6, 1H), 5.16 (dd, J=13.2, 6.6, 1H), 4.56 (t, J=5.1, 2H), 3.52-3.45 (m, 2H), 1.49 (d, J=6.6, 6H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1>O1CCCC1>[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([O:32][CH2:33][CH2:34][C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][C:38](=[O:44])[NH:39]3)=[CH:49][CH:48]=1
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OCCc2cccc3c2CC(=O)N3)cc1
Reaction time: 0.25 h
Yield: 16.5 %

Procedure:
Diethyl azodicarboxylate (0.47 mL, 3 mmol) was added to a solution of triphenylphosphine (0.786 g, 3 mmol) in tetrahydrofuran (10 mL) under nitrogen atmosphere. The mixture was stirred for 15 minutes. To it was then added 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (0.53 g, 3 mmol) followed by 4-methoxyphenol (0.372 g, 3 mmol). The mixture was stirred at room temperature for 18 hours and the solvent was evaporated. The residue was dissolved in ethyl acetate (150 mL) and the organic solvent was washed with 2 N hydrochloric acid (3×30 mL), saturated sodium bicarbonate solution and brine. The residue was chromatographed on silica gel eluting with ethyl acetate:hexane 2:8 to give 0.14 g (16%) 4-[2-(4-Methoxy-phenoxy)-ethyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[CH:29]O)[C:22](=[O:28])[NH:23]2>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[CH:29][NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:16][CH:15]=1)[C:22](=[O:28])[NH:23]2
Reactant: O=C1Nc2cccc(F)c2C1=CO
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Product: O=C1Nc2cccc(F)c2C1=CNc1ccc(OCCCN2CCCCC2)cc1

Procedure:
In a manner similar to that described in Example 231, 4-(3-piperidin-1-yl-propoxy)-phenylamine (610 mg, 1.3 equiv.) and 4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (360 mg, 2 mmol, 1 equiv.) are converted to the named compound as a yellow solid (625 mg, 79%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:28]([CH3:30])[CH3:29]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH:28]([CH3:30])[CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: CC(C)I
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 90 °C
Yield: 65.3 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.12 mmol), potassium carbonate (32 mg, 0.23 mmol) and 2-iodopropane (17 μL, 0.17 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 90° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using a hexanes/ethyl acetate/dichloromethane (3.5:0.5:4) afforded 24 mg (68%) of 3-(2-pyridyl)-5-(3-cyano-5-isopropoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.91 (m, 1H), 7.49 (m, 1H), 7.36 (s, 1H), 4.71 (m, 1H), 1.41 (m, 6H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([CH2:18][NH2:19])[CH2:17][CH2:16][CH2:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>CCOCC>[Cl:1][CH2:2][C:3]([NH:19][CH2:18][C:14]1([C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)[CH2:17][CH2:16][CH2:15]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NCC1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCl)NCC1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 4 h

Procedure:
A solution of chloroacetylchloride (3 g) in dry ether was added dropwise to a stirred solution of [1-(3,4-dichlorophenyl)cyclobutyl]methylamine (6.2 g prepared from the hydrochloride salt described above) and triethylamine (2.9 g) in dry ether (20 ml) at a temperature of 5° to 10° C. The mixture was stirred for four hours, filtered and the filtrate washed with water, dried and evaporated to give N-(2-chloroacetyl)[1-(3,4-dichlorophenyl)cyclobutyl]methylamine (m.p. 104°-105° C.).
Reaction SMILES: [O:1]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=O)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].O.[NH2:26][NH2:27]>C(O)C>[O:1]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:26][NH2:27])=[O:23])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 92 %

Procedure:
Compoud 1 (1 g) was dissolved in a mixture of ethanol (5 ml) and 85% hydrazine hydrate (2 ml). After 24 h the solvent was evaporated and residual traces of hydrazine removed by co-evaporation with toluene to give 8-hydrazinocarbonyloctyl β-D-galactopyranoside as a white solid which was recrystallized from ethanol, mp 194°, [α]D18 -2.16° (c 1.1, water), 92% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Cl[CH2:13][C:14]([OH:16])=[O:15].[OH-].[Na+]>O>[C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:13][C:14]([OH:16])=[O:15])(=[O:10])[CH3:9]
Reactant: O=C(O)CCl
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1cc(Br)ccc1OCC(=O)O
Temperature: 25 °C

Procedure:
A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (9.53 mmol) in water (70 mL) was treated with chloroacetic acid (11.64 mmol) and a solution of NaOH (21.25 mmol) in water (20 mL). The resulting yellow suspension was flushed with N2 and stirred at reflux overnight. Analysis by LCMS indicated the consumption of starting material and desired product formation. The reaction was cooled to room temperature and then acidified to pH˜3 with 1N aq HCl. The mixture was then cooled to 0° C. resulting in precipitate formation. A grey sticky solid was filtered and used without further purification. MS(ES)+ m/e 273/275 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH3:12])[N:10]=2)[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc2ccc(Cl)nn2c1=O
Temperature: 25 °C
Yield: 67.2 %

Procedure:
0.853 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was dissolved in 5 ml of N,N-dimethylformamide; 0.83 g of potassium carbonate was added; with stirring at room temperature, 0.5 ml of methyl iodide was added. After stirring at room temperature for 15 hours, ice water and saline were added; the reaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the crystal obtained was collected by filtration, washed with diethyl ether, and dried, to yield 0.62 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:26]1[CH:33]=[CH:32][C:29]([CH2:30][OH:31])=[CH:28][CH:27]=1.N1CCCC1>Cl[Pd]Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][OH:31])=[CH:28][CH:27]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: OCc1ccc(I)cc1
Reactant: C#CCOc1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl[Pd]Cl
Solvent: O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(OCC#Cc2ccc(CO)cc2)cc1
Yield: 20.5 %

Procedure:
General procedure A was followed using the product from step 3 Example 1 (266 mg, 1.0546 mmol), p-iodobenzylalcohol (156.5 mg, 0.669 mmol), PdCl2 (2.5 mg, 0.014 mmol), pyrrolidine (0.277 mL, 3.34 mmol), water (0.844 mL) to give the title compound (60 mg, 20.5%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:15])=[N:4][CH:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[N:4][C:3]=1[O:15][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCc1cnc(O)c(Br)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cnc(OCc2ccc(C(F)(F)F)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 101.1 %

Procedure:
A solution of Intermediate 36 (71.5 mg) in chloroform (7 ml) was added with 4-trifluoromethylbenzyl bromide (109.2 mg, TCI) and silver carbonate (120 mg, WAKO), and stirred at room temperature for 11 hours under light shielding. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=6:1) to obtain the title compound (Compound No. E-13, 114 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[O:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29](Cl)=[O:30]>>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:29]([CH:25]4[CH2:26][CH2:27][CH2:28][O:24]4)=[O:30])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)C1CCCO1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C1CCCO1
Yield: 33.2 %

Procedure:
As described for Example 8, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is reacted with 0.267 g of tetrahydrofurane-2-carbonyl chloride to give a glass which is crystallized from ethyl acetate to give 0.22 g of crystals, m.p. 208°-214° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>C(Cl)Cl>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[N:12]([CH:8]2[CH2:9][C:10]3[CH:11]=[C:2]([NH:1][C:37]([NH:36][CH2:34][CH3:35])=[O:38])[CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7]2)[CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(N)cc3C2)CC1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc2c(c1)CC(N(CCCN1CCN(C)CC1)C(=O)Nc1ccc(F)c(Cl)c1)CC2
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a solution of 1-(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea (from Preparative Example 27, 0.018 g, 0.038 mmol) in CH2Cl2 (0.2 mL) at 0° C. was added ethylisocyanate (0.0030 mL, 0.038 mmol). The mixture was stirred from 0° C. to room temperature for 16 hours, then concentrated in vacuo, and the residue was purified by preparative HPLC to give 0.019 g (92%) of 1-(7-{3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-ethyl-urea as a light yellow gum. 1H NMR (300 MHz, CD3OD): δ 7.60 (dd, 1H, J=6.6, 2.4 Hz), 7.30 (ddd, 1H, J=9.0, 4.2, 2.7 Hz), 7.18 (s, 1H), 7.15 (t, 1H, J=9.0 Hz), 7.06-6.97 (m, 2H), 4.30 (m, 1H), 3.60-3.40 (m, 10H), 3.20 (m, 4H), 3.05-2.85 (m, 7H), 2.07 (m, 4H), 1.15 (t, 3H, J=7.5 Hz). MS-ESI: 545.0 (M+H+).