Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:22]([NH:24][N:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26](=[O:39])[C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1C(OC(C)(C)C)=O)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[ClH:48]>O1CCOCC1.C(OCC)C>[ClH:48].[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:22]([NH:24][N:25]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:26](=[O:39])[C@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@H]1CCCN1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.656 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-(N-tert.-butoxycarbonyl-D-prolyl)-4-methylvalerohydrazide in 8 ml of dioxan was treated with 4 ml of 4M hydrogen chloride in dioxan. The mixture was stirred for 2 hours at room temperature and diluted with diethyl ether. The solid was filtered off, washed with diethyl ether and dried to give 0.367 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-2′-(D-prolyl)-4-methylvalerohydrazide hydrochloride in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]=[O:27].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][OH:27]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C=O)cc(OC)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(CO)cc(OC)c21
Temperature: 0 °C
Yield: 88.6 %

Procedure:
2.08 g (4.82 mmol) of 4-Bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde is dissolved in 60 ml Ethanol and NaBH4 (365 mg, 9.64 mmol) is added. After stirring for 30 min ice/water is added and the reaction mixture is extracted with ethyl acetate (3×). The organic layer is washed with water (3×) and brine (2×), dried (Na2SO4) and concentrated in vacuo. The residue is crystallized from diethyl ether/hexanes to give 1.85 g of colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[CH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:10]1>C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:14]1
Reactant: CCOC(=O)CCC=C[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reaction time: 72 h

Procedure:
First, 9 g of 2,3-difluoro-1-[trans-4-(4-ethoxycarbonyl-1-butenyl)cyclohexyl]benzene, 0.5 g of 10% Pd--C, and 50 ml of ethyl acetate were placed in a 300 ml autoclave. The mixture was stirred for 3 days under a hydrogen pressure of 30 kg/cm2. A catalyst was filtered away and a filtrate was concentrated. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/1) to obtain 7.71 g of 2,3-difluoro-1-[trans-4-(4-ethoxycarbonylbutyl)cyclohexyl]benzene (Y: 85.1%). The compound thus obtained had a purity of 85% by GC.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([O:21]C2C=CC=C(Cl)C=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (40 ML) was added to crude carbamate 10.5 (18.6 g; 59.7 mmol) cooled in an ice-water bath. After 1 min the reaction was stirred at rt for 15 min, then concentrated on a rotary evaporator. Ether (200 mL) was added and this washed with 3 M NaOH (3×50 mL) and water (50 mL). The product was extracted into 1 M HCl (3×50 mL) and the aq phase was basified with 3 M NaOH (60 mL). The free base was extracted into DCM (1×50 mL then 2×25 mL), dried (MgSO4), filtered and concentrated to an oil. The hydrochloride salt was precipitated from a methanolic (6 mL) solution of the free base by the dropwise addition of HCl in ether (200 mL of HCl-saturated ether plus 150 mL of ether). The salt was collected by filtration and washed with ether (100 mfL) giving an off-white solid (7.97 g; 68% from 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester). LC (method B) tR=8.2 min; 1H NMR (200 MHz, DMSO-d6) δ 8.94 (brs, 2H), 7.33 (m, 1H), 7.12 (m, 1H), 7.00 (m, 2H), 4.70 (m, 1H), 3.20 (m, 2H), 3.08 (m, 2H), 2.08 (m, 2H), 1.85 (m, 2H); ESIMS (free base) 212.0/213.9 (100/35) [MH+].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([O:13]CC)=[O:12])[S:8][C:7]=2[CH:16]=1)[CH3:2].O.[OH-].[Li+]>O1CCCC1.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[S:8][C:7]=2[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(CC)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc2cc(C(=O)O)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
The above 6-ethyl-2-ethoxycarbonylbenzo[b]thiophene (1.26 g) was dissolved in tetrahydrofuran (4 ml) and methanol (8 ml), and added thereto was lithium hydroxide monohydrate (677 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in water and the solution was made acidic with a 10% aqueous hydrochloric acid solution. The precipitates were collected by filtration and washed with water to give 6-ethylbenzo[b]thiophen-2-ylcarboxylic acid (1.15 g) as colorless crystals. ESI-I-Mass m/Z 205 (M−H).
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11]2)C#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[NH2-].[Na+].[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]\[C:37]([OH:39])=[O:38]>CCOCC.O>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]\[C:37]([OH:39])=[O:38].[CH:7]([CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11]1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CN1CCC(C(C#N)(c2ccccc2)c2ccccc2)C1
Agent: O=C(O)/C=C\C(=O)O
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(C)CN1CCC(C(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of 41.3 g. (0.13 mole) of α,α-diphenyl-α-(1-isobutyl-3-pyrrolidinyl)acetonitrile in 120 ml. of dry toluene was added 11.2 g. (0.286 mole) of sodium amide in a 500 ml. round bottom flask equipped with a reflux condenser and mechanical stirrer. The stirred mixture was refluxed for 46 hours. A large excess of water was added slowly and the water layer separated and discarded after being extracted with ether which was combined with the organic layer. The organic layer was washed with water and extracted with an excess of 2 N hydrochloric acid. The acid extract was basified with sodium hydroxide and the oil which separated was extracted with ether. The ethereal solutions were combined, concentrated and the residue was distilled. Yield, 25.8 g. (68%); b.p. 150°-152° C/0.05 mm. To 11.2 g. (0.0382 mole) of the above product was added 4.45 g. (0.0382 mole) of maleic acid in 150 ml. of absolute alcohol. After the amine dissolved, 100 ml. of dry ether was added. On standing in the refrigerator for several days the solution yielded a white solid which was recrystallized from ethyl acetate. Yield, 10.5 g. (67.25%); m.p. 119°-120° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:8]2)[CH2:4][CH2:3]1.O1CCC[CH2:23]1.C([Li])CCC.COS(OC)(=O)=O>CCCCCC>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:8]2)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CC1)OC(c1ccccc1)c1ccccc12
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: COS(=O)(=O)OC
Product: CN1CCC2(CC1)OC(C)(c1ccccc1)c1ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 1.4 g. of 1,3-dihydro-1'-methyl-3-phenylspiro[isobenzofuran-1,4'-piperidine], (Example 2), in 20 ml. of tetrahydrofuran is cooled to -50° and treated dropwise with 4 ml. of butyllithium in hexane. Stirring is continued for 30 minutes under nitrogen. To the solution is slowly added 900 mg. of dimethylsulfate in 10 ml. of tetrahydrofuran. The mixture is stirred at -10° for 1 hour and overnight at ambient temperature. Ice is added, the mixture is extracted with ether, and the organic solution is concentrated to an oil. The oil is converted to the hydrobromide salt and recrystallized from ethyl acetate to give crystals, m.p. 122°-125°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]1[C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=[N:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:25]3[O:21][N:22]=[CH:23][CH:24]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccno1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccno1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-isoxazolecarboxylic acid as starting materials, MS (LC/MS): 398.0 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:10]([CH2:13][C@@H:14]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])(O)=[O:11]>>[CH2:25]([C@H:14]([CH2:13][C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6]1)=[O:11])[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=C(O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Product: O=C(OCc1ccccc1)[C@@H](CC(=O)N1CCN(C2CC2)CC1)Cc1ccccc1

Procedure:
Using the mixed anhydride coupling procedure of Example with 1-cyclopropylpiperazine and benzyl (2R)-3-carboxy-2-benzylpropionate (Rosenberg et al., EP 307837, 1989) gave the desired product. 1H NMR (CDCl3) 7.10-7.34 (m, 5H), 5.11 (dd, 2H), 3.51 (m, 2H), 3.31 (m, 3H), 3.04 (dd, 1H), 2.74 (m, 2H), 2.52 (m, 3H), 2.35 (dd, 1H), 0.47 (m, 2H), 0.42 (m, 2H).
Reaction SMILES: [CH2:1]1[CH2:5][NH:4][C@H:3]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:2]1.Cl.CCN(C(C)C)C(C)C.[NH:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:27]([C:32](O)=[O:33])[C:28]([CH3:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CCOC(C)=O>[CH2:9]([O:8][C:6]([CH:3]1[CH2:2][CH2:1][CH2:5][N:4]1[C:32](=[O:33])[CH:27]([NH:26][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCCC1C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
To a suspension of H-pro-OBzl.HCl (2.00 g, 8.66 mmol) in CH2Cl2 (20 ml) was added DIEA (2.25 ml, 12.92 mmol) to give a colorless solution. Boc-tLeu-OH (1.95 g, 9.52 mmol), HOBT (1.76 g, 13.03 mmol) and EDC (2.49 g, 12.95 mmol) were added and the solution stirred under N2 at room temperature for 18 hours. Removed solvent in vacuo, dissolved in EtOAc and washed with H2O, 0.5N NaHSO4—(2×), saturated NaHCO3 (2×) and brine. Dried over anhydrous Na2SO4 and evaporated to give the title compound (3.57 g, 99% yield). 1H-NMR (500 MHz, CDCl3) δ 0.99 (s, 9H), 1.40 (8, 9H), 1.88-2.33 (m, 4H), 3.58-3.90 (m, 2H), 4.21-4.35 (d, 1H), 4.53-4.66 (m, 1H), 5.04-5.38 (m, 3H), 7.14-7.42 (m, 5H). LC-MS (ES+) m/e=419.4 (M+H).
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:24]2[C:19]([CH:20]=[N:21][C:22]([C:25]#[N:26])=[N:23]2)=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C([Sn](CCCC)=O)CCC>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:24]2[C:19]([CH:20]=[N:21][C:22]([C:25]3[NH:26][N:3]=[N:2][N:1]=3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccccc1-c1ccc2cnc(C#N)nn12
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1ccc2cnc(-c3nnn[nH]3)nn12
Temperature: 90 °C

Procedure:
Azidotrimethylsilane (0.250 mL, 1.88 mmol) was added to 7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine-2-carbonitrile (48.0 mg, 0.192 mmol) in Toluene (4.0 mL, 38 mmol) and Dibutyloxostannane (50.0 mg, 0.201 mmol) and heat at 90° C. for 4 h. Cool and conc. in vacuo, then purify by prep HPLC. The lyophilate was dissolved in MeOH, loaded onto a Phenomenex sulfonic acid resin, which was washed with MeOH and then the product eluted as the free base with 2M NH3 in MeOH. Conc. and reconc. from DCM afforded 7-(2-Methoxy-phenyl)-2-(1H-tetrazol-5-yl)-pyrrolo[2,1-f][1,2,4]triazine as a yellow film. LCMS (HPLC): 294 (M+H); 1H-NMR (DMSO-d6): 9.25 (s, 1H), 7.83 (m, 1H), 7.47 (m, 1H), 7.23 (m, 2H), 7.11 (m, 3H), 3.83 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[CH2:20]([NH2:22])[CH3:21]>C(Cl)(Cl)Cl>[CH2:20]([NH:22][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:21]
Reactant: CCN
Reactant: O=C(c1ccccc1)c1ccc(OCCCBr)cc1
Solvent: ClC(Cl)Cl
Product: CCNCCCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
1.0 g of 4-(3-bromopropyloxy)benzophenone was dissolved in a 70% aqueous ethylamine solution, and then stirred at 90° C. for 5 hours. The mixture was dissolved in 50 ml of chloroform, washed with water three times, dried over anhydrous sodium sulfate and then concentrated to obtain 0.9 g of N-ethyl-3-(4-benzoylphenyloxy)propylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=1)[CH:26](Cl)[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(OCC)C>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=1)[CH:26]([N:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:12]=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=2)[CH2:11][CH2:10]1)[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1ccc(C(Cl)c2cccc(OCc3ccccc3)c2)cc1
Reactant: Cc1cccc(CN2CCNCC2)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cccc(CN2CCN(C(c3ccc(Cl)cc3)c3cccc(OCc4ccccc4)c3)CC2)c1
Temperature: 25 °C
Yield: 53 %

Procedure:
The crude piperazine derivative from above (11.0 g, 56 mmole) was dissolved in 150 ml of toluene and added to 19.2 g (56 mmole) of 3-benzyloxy-4'-chlorobenzhydryl chloride (see U.S. Pat. No. 4,757,074) and heated to reflux for 40 hours. The reaction was cooled to room temperature, diluted to 600 ml with diethyl ether, and washed with 100 ml of 1.0M sodium hydroxide followed by three 200 ml portions of water and 100 ml of saturated sodium chloride. The product was dried over sodium sulfate and the solvent removed to give 27.0 g of crude product as a dark oil. The material was purified by chromatography on silica gel (Waters Prep 500) with 0.1% triethylamine in dichloromethane to give 14.7 g (53%) of 1-(3-benzyloxy-4'-chlorobenzhydryl)-4-(3-methylbenzyl)piperazine as a dark oil. A 5.0 g portion of the oil was dissolved in 300 ml of 2:1 ethanol:methanol and treated with an excess of ethanolic hydrochloric acid to produce the dihydrochloride salt of the product. Addition of 150 ml diethyl ether and cooling provided 1.74 g of the salt as white crystals, mp. 204°-208° C. Calc. for C32H33ClN2O 2HCl: C, 67.43; H, 6.19; N, 4.91; Cl, 18.66. Found: C, 67.15; H, 6.14; N, 4.87; Cl, 18.58.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:13]=[C:12]([CH3:22])[CH:11]=1)(=O)C.Cl>CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([NH:9][C:5]3[NH:6][CH2:7][CH2:8][N:4]=3)=[CH:11][C:12]([CH3:22])=[N:13]2)=[CH:20][CH:19]=1
Reactant: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2=NCCN2)n(-c2ccc(F)cc2)n1

Procedure:
1-Acetyl-2[1-(4-fluorophenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (21.0 g.) was treated with HCl in methanol as described in Example II to give 7.503 g. mp 213°-215°
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:17][O:15][C:14]([C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.1 g, 22.2 mmol) in DMF (60 mL) were added K2CO3 (12.3 g, 88.8 mmol) and MeI (1.7 mL, 26.6 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer washed with water (6 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product (5.4 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][N:18]=2)[C:9]([O:28][CH3:29])=[C:8]2[C:3]=1[C:4](=[O:36])[C:5](C(O)=O)=[CH:6][N:7]2[CH:30]1[CH2:32][CH2:31]1.[C-]#N.[Na+].O>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][N:18]=2)[C:9]([O:28][CH3:29])=[C:8]2[C:3]=1[C:4](=[O:36])[CH:5]=[CH:6][N:7]2[CH:30]1[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1ccc(NCCNc2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)nc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(NCCNc2c(F)c(N)c3c(=O)ccn(C4CC4)c3c2OC)nc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-7-[2-[(5-ethoxycarbonyl-2-pyridyl)amino]ethylamino]-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (540 mg, 1.08 mmol) and NaCN (540 mg, 11.0 mmol) in DMSO (10 mL) was stirred at 120° C. for 2 h. After cooling, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (2×50 mL). The organic layer washed with water (2×50 mL) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (hexane: EtOAc 1:3) of the residue gave crude product as a brown oil (600 mg). The obtained oil was further purified by column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.), hexane: EtOAc 1:3) to give ethyl 2-[2-[(5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinolin-7-yl)amino]ethylamino]pyridine-5-carboxylate (397 mg, 81%) as a yellow amorphous solid.
Reaction SMILES: CS[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[O:10]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][CH2:17][CH2:18][NH2:19])[CH2:11]1>C(O)C>[N+:5]([CH:4]=[C:3]1[NH:19][CH2:18][CH2:17][N:16]1[CH2:15][CH:12]1[CH2:13][CH2:14][O:10][CH2:11]1)([O-:7])=[O:6]
Reactant: NCCNCC1CCOC1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: O=[N+]([O-])C=C1NCCN1CC1CCOC1
Temperature: 85 °C
Yield: 81 %

Procedure:
2.5 g (0.0178 mol) of 1,1-dimethylthio-2-nitroethene, 2.56 g (0.0178 mol) of N1-((tetrahydrofuran-3-yl)methyl)ethane-1,2-diamine were added to 50 ml of ethanol. The resulting mixture was heated under reflux for 8 hours at 80-90 ° C. The mixture was then cooled to educe solid, concentrated, filtrated and dried to give a light yellow powder in 81% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.Cl[C:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:12]([Cl:21])[CH:11]=1>Cl.C(O)C>[Cl:21][C:12]1[CH:11]=[C:10]([NH:1][C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Cc1cccc(N)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1cccc(C)c1
Temperature: 80 °C

Procedure:
(Wallace, E., et. al., ibid.) m-toluidine (0.47 mL, 4.34 mmol) and conc. HCl (1 drop) were added to a solution of compound iii (1.00 g, 4.57 mmol) in ethanol (10 mL). The reaction mixture was heated at 80° C. for 3 h, cooled to room temperature and partitioned between water (15 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phase was dried (MgSO4) and reduced in vacuo to give the crude product as a brown oil. Column chromatography (SiO2), eluting with 12:1 Hexanes-EtOAc, gave compound iv. (0.670 g, 2.31 mmol, 51%) as a light orange oil, which solidified on standing, [M+H]+ m/z=291.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH3:19][C:20]1[C:24]([NH2:25])=[C:23]([CH3:26])[O:22][N:21]=1.C([O-])(=O)C.[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:25][C:24]3[C:20]([CH3:19])=[N:21][O:22][C:23]=3[CH3:26])[C:10]=2[N:11]=1
Reactant: Cc1noc(C)c1N
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1Nc1ncnc2ccc(Cl)nc12
Yield: 59.5 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.100 g, 0.500 mmol), 3,5-dimethylisoxazol-4-amine (0.140 g, 1.250 mmol) and sodium acetate (0.123 g, 1.50 mmol) in 5 ml of solvent (THF:H2O=1:1) was refluxed for 1 hour. The reaction mixture was diluted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crued was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to get N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-3,5-dimethylisoxazol-4-amine (0.082 g, 59%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.24 (3H, s), 2.40 (3H, s), 7.74 (1H, d, J=8.8 Hz), 7.93 (1H, brs), 8.16 ((1H, d, J=8.8 Hz), 8.69 (1H, s).