Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[NH:3]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25]Cl)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][N:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]2=[O:1])[CH2:21][CH2:22]1
Reactant: O=C1CCCC(=O)N1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1N1CCN(CCCN2C(=O)CCCC2=O)CC1
Temperature: 80 °C

Procedure:
Scheme-I: A mixture of 2,6-dioxopiperidine (2.60 g, 23.02 mmol), 1-[4-(2-methoxyphenyl)-piperazin-1-yl]-3-chloropropane (6.18 g, 23.02 mmol), potassium carbonate (2.3 8 g, 17.27 mmol) and tetrabutylammonium bromide (1.48 g, 4.60 mmol) in acetone (80 ml) was refluxed for 16 hours at 80° C. with stirring. The solvent was evaporated off in vacuo and the residue suspended in water (60 ml), extracted with chloroform (3×40 mmol) and the organic layers combined, washed with water (2.40 ml ), dried over anhydrous Na2SO4 and evaporated in vacuo to give the title compound. The product was purified by column chromatography over flash silica gel (230-400 mesh) using chloroform-methanol (98:1) as eluent; yield 3.58 g (45%), oil.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[C:17]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)(=[O:24])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:6]1[CH3:32].[OH-].[Li+]>O1CCCC1>[Cl:31][C:27]1[CH:26]=[C:25]([S:22]([C:17]2[C:16]([CH2:15][C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[N:5]([CH2:4][C:3]([OH:33])=[O:2])[C:6]=3[CH3:32])=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:24])=[O:23])[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2cccc(Cl)c2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2cccnc2S(=O)(=O)c2cccc(Cl)c2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A mixture of {3-[2-(3-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}acetic acid methyl ester (0.10 g) and tetrahydrofuran (5.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.31 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate and the combined extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 49:1 by volume) to afford the title compound as a white solid (0.085 g).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4](=[O:12])[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH:16][CH:17]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([O:23][CH2:24][C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)[C@H:20]([OH:21])[C@@H:18]1[OH:19].CN(C=O)C.ON1C2C=CC=CC=2N=N1.[NH:51]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:53](O)=[O:54].C(N=C=NCCCN(C)C)C>>[NH:51]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:53]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4](=[O:12])[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:54].[OH:16][CH:17]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([O:23][CH2:24][C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)[C@H:20]([OH:21])[C@@H:18]1[OH:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@@H](CC(=O)OC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(CO[C@H]2[C@H](O)[C@H](O)C(O)O[C@@H]2CO)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CC(=O)OC1CCCCC1)C(=O)O
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a cold solution of Asp(O-cHex)-Man(4-MBzl) (46.7 g, 86.4 mmol) in DMF (100 mL) diisopropylethylamine (15 mL, 86.1 mmol) was added. N-Hydroxybezotriazole (14.0 g, 104 mmol) was added followed by Boc-Gly (16.6 g, 94.8 mmol). The reaction mixture was stirred in the cold for a few minutes, and N-ethyl-N'-(dimethylaminopropyl)carbodiimide (18.2 g, 94.9 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was concentrated to a small volume and poured into 1.5 L of aqueous 10% K2CO3. The precipitated product was collected by filtration and was washed with water to a neutral pH to afford the titled compound (50.6 g).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=2[CH3:21])[C:8](=[O:22])[CH:7]=1.[Br:28]N1C(=O)CCC1=O>C(Cl)Cl>[Br:28][C:7]1[C:8](=[O:22])[N:9]([C:13]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=2[CH3:21])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Solvent: ClCCl
Product: Cc1ccc(CO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 80.2 %

Procedure:
4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-methyl-pyridin-2(1H)-one (from Step 2) (4.0 g, 10.8 mmol) was stirred at room temperature with N-bromosuccinimide (2.1 g, 11.9 mmol) in 100 ml of CH2Cl2 for 2.0 hours. The reaction was evaporated on a rotary evaporator and the resulting solid was washed with acetonitrile and dried in vacuo to yield a white solid (3.9 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.67 (app q, J=6.24 Hz, 1H), 7.35 (d, J=1.01 Hz, 2H), 7.10 (s, 1H), 7.04 (m, 1H), 6.91 (ddd, J=11.08, 8.66, 2.42 Hz, 1H), 6.15 (d, J=0.63 Hz, 2H), 5.29 (s, 2H), 4.66 (s, 2H), 2.08 (s, 3H), 1.97 (s, 3H); ES-MS m/z 450 (M+H). ES-HRMS m/z 450.0467 (M+H calcd for C21H19BrF2NO3 requires 450.0511).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([F:14])[F:13])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([F:14])[F:13])[C:5]([Cl:18])=[O:6]
Reactant: O=C(O)c1ccc(OC(F)F)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OC(F)F)c(Cl)c1
Yield: 125.3 %

Procedure:
3-Chloro-4-[(difluoromethyl)oxy]benzoic acid (D17; 0.28 g, 1.258 mmol) was stirred at room temperature with oxalyl chloride (0.220 mL, 2.52 mmol) and N,N-dimethylformamide (DMF) (0.05 ml) in dry dichloromethane (DCM) (5 ml) under nitrogen for 16 h. The solvent was evaporated in vacuo to give a yellow semi-solid (380 mg) which was used crude in the subsequent reaction D47.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][NH2:13]>>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:13][CH3:12])[C:5]2=[N:4][CH:3]=1
Reactant: Brc1cncc2ncc(Br)n12
Reactant: CN
Product: CNc1nccn2c(Br)cnc12
Reaction time: 12 h
Yield: 40 %

Procedure:
A mixture of 1 g (3,6 mmol) of 3,5-dibromoimidazo[1,2-a]pyrazine in 9 ml of a 40% strength aqueous methylamine solution is maintained with stirring for 12 hours. After evaporation under reduced pressure and chromatography on a silica column eluted with ether, 0.33 g (Yld=40%) of 3-bromo-8-methylaminoimidazo[1,2-a]pyrazine (m.p. 139° C.) is obtained.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6]([F:27])([F:26])[CH2:7]2.[N:28]1[CH:29]=[C:30]([C:37](O)=[O:38])[N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=12>>[F:26][C:6]1([F:27])[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:37]([C:30]2[N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]3=[N:28][CH:29]=2)=[O:38])[CH2:7]1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CNC(=O)c2cnc3ccccn23)c1

Procedure:
prepared by reaction of (1S,2S,5R)-(2-aminomethyl-7,7-difluoro-3-aza-bicyclo[3.3.0]-oct-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with imidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:14](=O)[CH2:15][O:16][CH2:17][CH2:18][N:19]=[N+:20]=[N-:21])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[CH3:2].S(O)(O)(=O)=O.[CH3:29][O:30][C:31](=[NH:33])[NH2:32].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C.CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[NH:33][C:31]([O:30][CH3:29])=[N:32][C:14]=1[CH2:15][O:16][CH2:17][CH2:18][N:19]=[N+:20]=[N-:21])=[O:23])[CH3:2]
Reactant: COC(=N)N
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1=C(COCCN=[N+]=[N-])N=C(OC)NC1c1ccccc1Cl
Temperature: 80 °C

Procedure:
A mixture of 2-[2-(2-azido-ethoxy)-acetyl]-3-(2-chloro-phenyl)-acrylic acid ethyl ester (1.50 g, 4.44 mmol), O-methylisourea sulfate (0.82 g, 6.66 mmol) and sodium bicarbonate (1.5 g, 17.86 mmol) in N,N-dimethylacetamide (25 mL) was heated to 80° C. and maintained at this temperature overnight (ca. 15 h). The mixture was cooled to RT and then taken up in EtOAc (100 mL) and H2O (50 mL). The EtOAc extract was washed with brine (50 mL), dried (Na2SO4), filtered, concentrated and dried in vacuo. The crude product was purified by chromatography using the ISCO Combiflash SQ16× (120 g Redisep silica gel column, 0 to 60% EtOAc in hexanes for 30 min at 40 mL/min) to afford 1.189 g (68% for 2 steps) of white solid as a purified product.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[C:21]([F:20])([F:30])[F:31])[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccccc1C(F)(F)F
Product: FC(F)(F)c1ccccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[2-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[NH:7][S:4]([CH:1]1[CH2:3][CH2:2]1)(=[O:6])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NS(=O)(=O)C1CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of cyclopropanesulfonamide (6.51 g, triethylamine (40 mL) and DMAP (0.656 g) in DCM (150 mL) was slowly added benzyl chloroformate (12 mL). The mixture was stirred at room temperature for 18 hours. The mixture was washed with 1 N HCl. The aqueous layer (pH 1) was extracted with EtOAc (×2). The combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated. The resulting residue was purified by flash chromatography (ISCO, 0-10% methanol in dichloromethane) to afford the desired product (7.8 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.56-7.44 (m, 1H), 7.38 (s, 5H), 5.22 (s, 2H), 2.92-2.84 (m, 1H), 1.40-1.35 (m, 2H), 1.12-1.06 (m, 2H).
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][CH2:16][O:17][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]=O)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][CH2:16][O:17][C:10]=3[CH:9]=2)[CH:28]([C:26]2[CH:25]=[CH:24][C:23]3[O:18][CH2:19][CH2:20][O:21][C:22]=3[CH:27]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCCO2
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: CC(C)N1C(=O)NC(c2ccc3c(c2)OCCO3)c2cc3c(cc21)OCCO3
Yield: 14 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(ethylenedioxy)-phenyl]urea (132 mg) and 1,4-benzodioxan-6-carboxaldehyde (113 mg) by the procedure described in example 10 in 14% yield,. mp: 92-95° C. 1H NMR (CDCl3): 6.85-6.76 (m, 3H), 6.62 (s, 1H), 6.32 (s, 1H), 5.20 (s, 1H), 4.99 (s, 1H), 4.46 (m, 1H), 4.24 (s, 4H), 4.23-4.17 (m, 4H), 1.56 (d, J=6.9, 3H), 1.54 (d, J=6.9, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][C:12]1[C:17]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>C(#N)C.O>[Cl:11][C:12]1[C:17]([S:18]([NH:21][C:22]([NH:1][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)=[O:23])(=[O:19])=[O:20])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2Cl)n1

Procedure:
To a stirred suspension of 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 20 ml of dry acetonitrile at room temperature was added 2.2 g of 2-chloropyridine-3-sulfonylisocyanate. The mixture was stirred for several hours and filtered. Evaporation of the filtrate yielded a solid residue which was stirred in approximately 30 ml of water while adjusting the pH of this mixture to 11 by the addition of 10% of NaOH. This solution was filtered, the filtrate pH adjusted to pH 7 by adding 10% hydrochloric acid and the resulting neutral solution was again filtered. The desired product was then precipitated from this filtrate by adjusting the pH to 2, collected in a sintered funnel and dried in a vacuum oven at room temperature. It melted at 165°-168°.
Reaction SMILES: [OH:1][C:2](CC1C=CC=CC=1)([C:19]1[CH:24]=[CH:23][C:22]([O:25]CC2C=CC=CC=2)=[CH:21][CH:20]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][CH2:9]1.[H][H].C([O-])=O>CO.[Pd]>[OH:1][CH:2]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C1NCN(CCCNCC(O)(Cc2ccccc2)c2ccc(OCc3ccccc3)cc2)c2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: O=C1NCN(CCCNCC(O)c2ccc(O)cc2)c2ccccc21
Yield: 78.9 %

Procedure:
15.5 gm of 1-{-[2-hydroxy-2-(4-benzyloxy-phenyl)-benzylethylamino]-propyl}-1,2,3,4-tetrahydro-4-quinazolone (m.p. 119°-121° C.) were dissolved in 250 ml of methanol and debenzylated by hydrogenation at 60° C. and 6 bars pressure in the presence of palladium as the catalyst. After 2 mols of hydrogen had been taken up, the hydrogenation was complete, yielding of 8 gm of 1-{3-[2-hydroxy-2-(4-hydroxyphenyl)-ethylamino]-propyl}-1,2,3,4-tetrahydro-4-quinazolone, whose formate of the formula ##STR71## had a melting point of 174°-176° C. The yield was 61.5% of theory.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]([O:11]CC)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+:15]>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:8][C:9]([O-:11])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na+:15]
Reactant: CCOC(=O)Cc1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])Cc1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 2-(3-chloropyridin-2-yl)acetate (7.59 g, 38 mmol) in THF (76 mL) was treated at room temperature with 3 M aqueous NaOH (25.3 mL, 76 mmol). The mixture was stirred at room temperature overnight and concentrated to remove the THF. The aqueous residue was frozen on dry ice and lyophilized to give sodium 2-(3-chloropyridin-2-yl)acetate as an off-white solid, used without further purification. Mass spectrum m/z 172 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1.C([O-])(=O)C.[NH4+].C(O)C>C(OCC)C>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:29]([C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)[CH:27]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccc(-n2cccn2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOCC
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccc(-n5cccn5)c4)nc23)[C@H]2C=C[C@@H]1C2
Temperature: 80 °C

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 3-Pyrazol-1-yl-benzaldehyde (32.2 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were combined in Ethanol (2.21 mL, 37.8 mmol) in a reaction tube and heated at 80° C. overnight. Upon cooling, a precipitate formed. Reaction was diluted with 3 ml ethyl ether and cooled in an ice/water bath. The resulting solid was filtered, washed with cold ether and dried under hi-vacuum. Product is a white solid. Yield: 41.35 mg (54%) of the title compound. (300 MHz, DMSO-d6) 13.39 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J=8 Hz, 1H), 7.81 (m, 2H), 7.67 (t, J=16 Hz, 8 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.25 (s, 1H), 6.62 (s, 1H), 6.53 (s, 1H), 6.39 (s, 1H), 5.15 (t, J=17 Hz, J=9 Hz, 1H), 2.89 (d, J=17 Hz, 2H), 2.63 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=446 (M+H), HPLC: 2.51 min. (G Method)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[CH:10](O)=O>>[Br:1][C:2]1[C:3]2[N:9]=[CH:10][NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: Nc1cccc(Br)c1N
Product: Brc1cccc2[nH]cnc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 3-bromobenzene-1,2-diamine (2 g, 10.7 mmol) in HCOOH was stirred at 100° C. for 1 h. The mixture was cooled and concentrated in vacuo and diluted with ethyl acetate and aq. NaHCO3. The mixture was extracted further with ethyl acetate and the combined organic layers dried and concentrated to give the crude product which was purified by column chromatography to obtain the desired product (1.65 g, Yield 80%). LCMS (m/z): 197.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24]([O:26]CC)=[O:25])[CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24]([OH:26])=[O:25])[CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)O)cnc3c2)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of ethyl 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoline-3-carboxylate (385 mg, 1 mmol), NaOH (2M, 5 mL) in EtOH (15 mL) and THF (15 mL) was stirred at 60° C. for 5 h. The mixture was concentrated to a residue, to which was added aq.sat. citric acid (10 mL). The solution was extracted with EA(25 mL×2), separated, dried, filtered and concentrated to give the compound 7-(4-(tert-butoxycarbonyl)-piperazin-1-yl)quinoline-3-carboxylic acid (286 mg, 80%) as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([OH:19])=O)[CH:5]=[CH:6][C:7]=1[O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:16][C:17]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]3)=[CH:25][N:26]=2)=[O:19])=[CH:3][C:2]=1[Cl:1])(=[O:10])=[O:11]
Reactant: O=C(O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c3)nc2)CC1

Procedure:
A solution of 2-(3-chloro-4-(trifluoromethylsulfonyloxy)phenyl)acetic acid 237-1, 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (112 mg, 0.51 mmol), HATU (232 mg, 0.61 mmol) and DIEA (0.26 ml, 1.49 mmol) in DMF (2.0 ml) was stirred at room temperature overnight. The solution was subjected directly to reverse phase HPLC to give 4-(2-(5-(4-acetylpiperazin-1-yl)pyridin-2-ylamino)-2-oxoethyl)-2-chlorophenyl trifluoromethanesulfonate 237-2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:34].C(N(CC)C(C)C)(C)C.CO.C(OCC)(=O)C>C(#N)C>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:48][CH2:49]2)([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3cccnc3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4cccnc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 24 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.54 g, 1.16 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.95 g, 1.74 mmol), and N,N-diisopropylethylamine (0.81 mL, 4.64 mmol) in acetonitrile (16 mL). Heat to reflux. After 24 hour, evaporate in vacuo, dilute with dichloromethane, and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 6/1/0.5 methanol/ethyl acetate/concentrated aqueous ammonia to give the title compound: Rf=0.27 (silica gel, 6/1/0.5 methanol/ethyl acetate/concentrated aqueous ammonia).