Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.C[CH:20]([C:24](Cl)=[O:25])[C:21](Cl)=[O:22].[Li+].[OH-:28]>ClCCl.O>[O:25]=[C:24]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH2:20][C:21]([OH:22])=[O:28]
Reactant: CC(C(=O)Cl)C(=O)Cl
Reactant: [OH-]
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
To a solution of 3-trifluoromethyl-phenylamine (11.6 mL; 93 mmol; 1 eq) and triethylamine (12.9 mL; 93 mmol; 1 eq) in dichloromethane (467 mL), methyl malonyl chloride (10.0 mL; 93 mmol; 1 eq.) is added at 0° C., under argon. The solution is allowed to stir for 10 minutes at room temperature. The crude mixture is then treated with water (115 mL) before removing the dichloromethane (15 mL) in vacuum. The resulting aqueous solution is cooled to 0° C. and diluted with methanol (235 mL) before adding dropwise a 1.5 M aqueous solution of LiOH (4.47 g; 186 mmol; 2 eq.). The solution is allowed to stir at room temperature for 1 hour. After removal of methanol under reduced pressure, the pH of the resulting aqueous solution is adjusted to 1 using a concentrated solution of HCl (16 mL). The acidic solution is extracted with dichloromethane (3×300 mL). The combined organic extracts are dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound as a white powder (21.8 g; 88 mmol; 95%).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:12][N:13]([CH2:15][CH:16]1[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)(O)[CH2:21][CH:20]2[CH2:31][CH:17]1[CH2:18][CH2:19]2)[CH3:14].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH3:14][N:13]([CH2:15][CH:16]1[CH:17]2[CH2:31][CH:20]([CH2:19][CH2:18]2)[CH:21]=[C:22]1[C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1)[CH3:12].[CH3:14][N:13]([CH2:15][C:16]1[CH:17]2[CH2:31][CH:20]([CH2:21][C:22]=1[C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1)[CH2:19][CH2:18]2)[CH3:12]
Reactant: CN(C)CC1C2CCC(C2)CC1(O)c1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN(C)CC1=C(c2cccc(O)c2)CC2CCC1C2
Product: CN(C)CC1C(c2cccc(O)c2)=CC2CCC1C2
Yield: 11.5 %
Yield: 50.2 %

Procedure:
Add TsOH (5.0 g, 29.1 mmol) to a solution of 2-dimethylaminomethyl-3-(3-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol (4.8 g, 17.5 mmol) in toluene (150 mL). Heat the reaction mixture to reflux for 2 hours and then quench the reaction by addition of saturated aqueous K2CO3 (20 mL). Extract the aqueous layer with EtOAc (60 mL×3). The combined organic layers are washed with brine, dried over Na2SO4 and evaporated under vacuum. Purify the residue by preparative HPLC to yield 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol (2.27 g, 50.2%; MS (m/z): 258 (M+1)) and 3-(2-((dimethylamino)methyl)bicyclo[3.2.1]oct-2-en-3-yl)phenol (517 mg, 11.5%; MS (m/z): 258 (M+1)) as white solid. Two isomers show comparable biological activity in bioassay.
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[C:11]1[CH:16]=[CH:15][C:14]([C:17]2(O)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:39]=4)=[CH:34][CH:33]=3)(O)[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=1.I.[PH2](O)=O>C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18]3[C:23]([C:24]([C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:47]=[CH:46][C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[CH:39]=5)=[CH:34][CH:33]=4)=[C:25]4[C:30]=2[CH:29]=[CH:28][CH:27]=[CH:26]4)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=1
Reactant: OC1(c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc2C(O)(c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1ccc2cc(-c3ccc(-c4c5ccccc5c(-c5ccc(-c6ccc7ccccc7c6)cc5)c5ccccc45)cc3)ccc2c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 99.4 %

Procedure:
9,10-bis(4-(2-Naphthyl)phenyl)-9,10-dihydroxy-9,10-dihydro-anthracene (3.5 g, 5.7 mmole) was suspended in acetic acid (80 ml). To the resultant suspension, a 57% hydroiodic acid (15 ml, 0.11 mole, 20 eq) was added and the obtained mixture was stirred at 100° C. for 7 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (30 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a white solid (3.3 g, 98%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[CH:16]=[C:15]([CH3:18])[S:14][C:13]=3[NH:12][C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH2:4][C@@H:3]1[CH2:23][OH:24].[CH3:25]OC[C@@H]1NCCN(C2C3C=C(C)SC=3NC3C=CC=CC=3N=2)C1>>[CH3:25][O:24][CH2:23][C@@H:3]1[N:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[CH:16]=[C:15]([CH3:18])[S:14][C:13]=3[NH:12][C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH2:4]1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CO)C1
Reactant: COC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1
Product: COC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1C

Procedure:
Using a similar method to (R)-[1-methyl-4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-methanol, using (R)-10-(3-methoxymethyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (800 mg) affords the title compound as a yellow solid (758 mg): mp 76-80° C.; 1H NMR (CDCl3) δ 2.31 (s, 3H), 2.42-2.27 (m, 2H), 2.39 (s, 3H), 2.84 (dt, 1H), 2.99 (dd, 1H), 3.14 (ddd, 1H), 3.36 (s, 3H), 3.46 (dd, 1H), 3.54 (dd, 1H), 3.91 (d, 1H), 4.02 (d, 1H), 4.96 (s, 1H), 6.30 (d, 1H), 6.60 (dd, 1H), 6.87 (dt, 1H), 6.96 (dt, 1H), 7.04 (dd, 1H); MS (APCI) m/z (rel intensity) 357.2 (100).
Reaction SMILES: F[C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].SC1SC2C(C)=CC=CC=2N=1.[Cl:21][C:22]1[S:23]C2C=CC(Cl)=CC=2N=1>>[Cl:21][C:22]1[S:23][C:2]2[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: Cc1cccc(N)c1F
Agent: Cc1cccc2nc(S)sc12
Product: Cc1cccc2nc(Cl)sc12
Temperature: 180 °C

Procedure:
The title compound was prepared from 2-fluoro-3-methylaniline via 2-mercapto-7-methyl-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 180° C. for 24 h in a sealed tube.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([Cu])#[N:13]>N1C=CC=CC=1>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc2ncccc2c1
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: N#Cc1ccc2ncccc2c1
Temperature: 200 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-bromoquinoline (2.0 g, 9.61 mmol) in pyridine (30 mL) was added CuCN (3.0 g, 33.6 mmol) at RT under inert atmosphere. The reaction mixture was gradually heated to 200° C. and stirred for 8 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with ice-cold H2O (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with H2O (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 30% EtOAc/hexane) afforded compound I-C (1.25 g, 8.0 mmol, 83%) as white solid. 1H NMR (200 MHz, CDCl3): δ 9.08-9.05 (m, 1H), 8.25-8.19 (m, 3H), 7.86 (dd, J=8.6, 1.8 Hz, 1H), 7.55 (dd, J=8.6, 1.8 Hz, 1H). MS (ESI): 155 [M+H]+.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].FC(F)(F)C(O)=O.[OH:13][CH2:14][C@@H:15]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][CH:4]([O:13][CH2:14][C@@H:15]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16]1)[CH3:5])[CH3:2]
Reactant: O=C1CCC[C@H](CO)N1
Reactant: C=COCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(C)OC[C@H]1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
Ethyl vinyl ether (1.68 mL, 17.5 mmol) and trifluoroacetic acid (0.1 mL) were added sequentially to a solution of (R)-6-hydroxymethylpiperidin-2-one (prepared from D-α-aminoadipic acid according to Huang, et al., Synth. Commun. 1989, 19, 3485–3496, 1.62 g, 12.5 mmol) in CHCl3 (10 mL) at rt. The reaction mixture was stirred at rt for 18 h, then saturated aqueous NaHCO3 (100 mL) was added and the mixture was extracted with CH2Cl2 (3×75 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→4% MeOH/CH2Cl2, gradient) afforded 2.03 g (80%) of (R)-6-(1-ethoxyethoxymethyl)-piperidin-2-one.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].O.BrC[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:9]1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCC(=O)N(c1ccccc1)[C@@H]1CCCN(CCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
3(R)-(Phenyl-propionyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (169) (100 mg) was dissolved in a mixture of TFA-CH2Cl2 (1 ml, 20%) and stirred for 1 hr. After removal of solvent, the residue was dried under vacuum for 30 min and dissolved in 5 ml of CH2Cl2, washed with sat. K2CO3, dried (Na2SO4), filtered. After evaporation of the solvent, the residue was dissolved in CH3CN (1 ml). Then K2CO3 (125 mg, 3 eq), water (1 ml) and (2-bromoethyl)benzene (0.05 ml, 1.2 eq) was added. The mixture was heated at 70° C. for 12 hr. After cooling to room temperature, the mixture was diluted with sat. NAHCO3 (5 ml), extracted with CH2Cl2 (2×10 ml). The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by silica gel chromatography (100% CH2Cl2, 2%-4% MeOH in CH2Cl2) to give 170 as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ7.40 (m, 3H), 7.10 (m, 2H), 4.80 (m, 1H), 0.20 (m, 1H), 4.00 (m, 1H), 2.40 (m, 2H), 1.95 (m, 3H), 1.61 (m, 1H), 1.51 (m, 1H), 1.50 (s, 9H), 1.30 (m, 1H), 1.00 (t, 3H) ppm; LRMS (calculated for C22H28N2O2)+336, found 336; IR (film) 2978, 2937, 2860, 1693, 1662, 1698, 1494, 1422, 1363, 1264, 1151, 1386, 1182 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C:7]2=[N:14][OH:15]
Reactant: O=C1CCOc2c(F)cccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: ON=C1CCOc2c(F)cccc21
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 8-fluorochroman-4-one (8.2 g), hydroxylamine hydrochloride (3.78 g) and sodium acetate (4.46 g). A reflux condenser was added, the flask was purged with argon, dry EtOH (20 mL) was added, and the mixture was stirred at reflux for 18 hours. The solution was cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was dried, and evaporated to give the intermediate 8-fluorochroman-4-one oxime, which was reduced with Raney Nickel in EtOH at 50 PSI to yield the titled amine (4.69 g, 57%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]1[C@H:41]2[C@@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][CH2:34][NH:33]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:7]2[O:6][C:5]([C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])=[C:9]([CH2:10][C:11]([N:33]3[CH2:34][CH2:35][C@H:36]4[C@@H:41]([CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:32]3)=[O:12])[C:8]=2[CH:14]=1
Reactant: C1CC[C@H]2CNCC[C@@H]2C1
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)N3CC[C@@H]4CCCC[C@H]4C3)c2c1
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.3 mg trans-decahydroisoquinoline followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.34 min. (m/Z=412.3, 328.2, 434.2).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[CH:13]=O.[C:15]([O-:18])(=[O:17])[CH3:16].[CH:19]1C=CC=CC=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[CH:13]=[CH:16]/[C:15]([O:18][CH3:19])=[O:17]
Reactant: O=C/C=C/c1ccc2ccccc2n1
Reactant: CC(=O)[O-]
Reactant: c1ccccc1
Product: COC(=O)/C=C/C=C/c1ccc2ccccc2n1
Yield: 56 %

Procedure:
A solution of (E)-3-(2-quinolinyl)-2-propenal (23) and methyl (triphenylphrophoranylidene) acetate (1.10 g, 3.27 mmol) in benzene (15 ml) was stirred for 6 hours at room temperature. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel with diethyl ether-petrol ether (1:2) as eluent to give the title compound (0.44 g, 56%). 1H NMR (DMSO-d6, HMDSO), δ: 3.72 (3H, s); 6.32 (1H, d, J=16.0 Hz); 7.45 (1H, d, J=10.0 Hz); 7:52-4.85 (5H, m); 7.85-7.18 (2H, m); 8.35 (1H, d, J=9.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([N:23]1[CH2:27][CH2:26][CH:25](O)[CH2:24]1)[CH3:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:25]2[CH2:26][CH2:27][N:23]([CH2:21][CH3:22])[CH2:24]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN1CCC(O)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Product: CCN1CCC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)C1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 1-Ethyl-3-pyrrolidinol.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:9])([CH3:8])[CH3:7].C([O-])([O-])=O.[K+].[K+].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CC#N>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[C:6]([OH:9])([CH3:8])[CH3:7])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: CC(C)(O)C1CCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(O)C1CCCN1Cc1ccc([N+](=O)[O-])cc1
Yield: 50.9 %

Procedure:
2-Pyrrolidin-2-yl-propan-2-ol (100 mg, 0.78 mmol) is dissolved in CH3CN (5 mL) to which K2CO3 (300 mg, 2.17 mmol) and p-nitrobenzylbromide (250 mg, 1.16 mmol) were added. The resulting mixture is stirred until MS suggested no starting alcohol is present. The suspension is filtered to remove the potassium salts and the acetonitrile is removed under vacuum. The residue is purified to afford the product (105 mg, 51%). 1H NMR (300 MHz, CDCl3) 8.18 (2H, d, J=8.7 Hz), 7.54 (2H, d, J=8.7 Hz), 4.25 (1H, d, J=15 Hz), 3.72 (1H, d, J=15 Hz), 2.90-2.95 (1H, m), 2.76-2.80 (1H, m), 2.28-2.38 (2H, m), 1.71-1.91 (4H, m), 1.24 (3H, s), 1.20 (3H, s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH2:11])=[C:3]([NH2:12])[CH:2]=1.[N:13]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[C:16]([NH2:23])=[C:15]([NH2:24])[CH:14]=1>>[NH:11]1[C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[N:1]=[CH:2][C:3]=2[N:12]=[CH:14]1.[NH:23]1[C:16]2[C:17]3[N:18]=[CH:19][CH:20]=[CH:21][C:22]=3[N:13]=[CH:14][C:15]=2[N:24]=[CH:2]1
Reactant: Nc1cnc2cccnc2c1N
Reactant: Nc1cnc2ccccc2c1N
Product: c1ccc2c(c1)ncc1nc[nH]c12
Product: c1cnc2c(c1)ncc1nc[nH]c12

Procedure:
In step (4) of Reaction Scheme I, a quinoline-3,4-diamine or [1,5]naphthyridine-3,4-diamine of Formula XIX is reacted with a carboxylic acid equivalent, which is selected such that it will provide the desired —X-Hal substituent in a 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XX. Suitable carboxylic acid equivalents include ortho esters, acid halides, imidates, and imidate salts.
Reaction SMILES: [NH2:1][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]=[C:4]([Cl:16])[N:3]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:32](=[O:33])[CH2:31][C:26]3([CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:25][C:24]2=[O:34])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:16].[NH2:1][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]=[C:4]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:24](=[O:34])[CH2:25][C:26]4([CH2:30][CH2:29][CH2:28][CH2:27]4)[CH2:31][C:32]3=[O:33])[CH2:19][CH2:18]2)[N:3]=1
Reactant: O=C1CC2(CCCC2)CC(=O)N1C1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nc(N3CCC(N4C(=O)CC5(CCCC5)CC4=O)CC3)nc(N)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 70 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline, 73.2 g of 8-(4-piperidinyl)-8-azaspiro[4,5]decan-7,9-dione, 62.1 g of anhydrous sodium carbonate and 800 ml of dimethylformamide is stirred under nitrogen at 135° for 8 hours. It is allowed to cool to room temperature, filtered and the filtrate evaporated. The residue is poured with stirring and cooling into 300 ml of water, the mixture diluted with 1400 ml of water and filtered. The solids are triturated with 1600 ml of ethyl acetate and 10 ml of saturated aqueous sodium carbonate. The organic layer is separated, dried, evaporated and the residue dissolved in 1,000 ml of ethyl acetate. The solution is acidified with hydrogen chloride, the precipitate filtered off and recrystallized from aqueous methanol, to yield the 8-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidinyl]-8-azaspiro[4,5]decan-7,9-dione hydrochloride melting at 277°-279° (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:14]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17]>CN(C)C=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][CH:14]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])=[N:3][CH:4]=1
Reactant: Nc1ncnc2ccccc12
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)C(=CNc1ncnc2ccccc12)C(=O)OC
Temperature: 150 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 4-aminoquinazoline (7.27 g) and dimethyl methoxymethylenepropanedioate (9.6 g) in N,N-dimethylformamide (35 ml) was stirred for 2 hours at 150° C. The reaction mixture was cooled to ambient temperature and poured into ice-water to give crystals, which were separated by filtration, washed with water and dried to ambient temperature to give a mixture (13.3 g) of dimethyl [(4-quinazolinylamino)methylene]propanedioate and methyl 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]([F:31])([F:30])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:27][C:26]1[CH:25]=[CH:24][C:23]([CH:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C:7]([F:31])([F:30])[F:6])=[N:9][N:10]=4)[N:13]=3)[CH2:22][CH2:21]2)=[CH:29][CH:28]=1)=[O:4]
Reactant: Nc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A solution of chloroacetyl chloride (140 mg, 1.24 mmol) in DCM (2 mL) was added dropwise to a stirred suspension of 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]aniline (obtained as described in Example 615) (375 mg, 1.03 mmol) and pyridine (164 mg, 2.07 mmol) in DCM (3 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 2 hours. The resulting precipitate was collected by filtration, washed with DCM (2 mL) and dried under vacuum to give 2-chloro-N-[4-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]acetamide (418 mg, 92%) as a solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[C:12]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[C:33]([CH3:34])=[C:32]([C:35](=[O:39])[CH2:36][CH2:37][CH3:38])[CH:31]=[N:30]3)=[CH:25][CH:24]=2)=[O:21])=[CH:11]1)(=O)C>CCOC(C)=O.CO>[C:35]([C:32]1[CH:31]=[N:30][N:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:20]([C:12]3[C:13]4[C:18](=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=4)[NH:10][CH:11]=3)=[O:21])=[CH:24][CH:25]=2)[C:33]=1[CH3:34])(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(=O)c1cnn(-c2ccc(NC(=O)c3cn(C(C)=O)c4cc(C)ccc34)cc2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCC(=O)c1cnn(-c2ccc(NC(=O)c3c[nH]c4cc(C)ccc34)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
1.5 g of K2CO3 is added to a solution of 1.15 g of the compound from step 1 in 40 ml of MeOH/THF mixture (50/50; v/v) and stirred for 4 hours at RT. The reaction mixture is concentrated under vacuum, the residue is taken up in EtOAc/water mixture, the organic phase is washed with water, with saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is taken up in iso ether and the precipitate that formed is drained. 0.9 g of the expected compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:47])[C@@H:4]2[CH:22]([NH:23][C:24](=[O:45])[CH:25]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][CH3:42])[C:37](=[O:43])[C:36]3=[O:44])=[O:34])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21](=[O:46])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[O:8].O1CCCC1.C(O)(=O)C>CCOCC.[Zn]>[CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:8])[N:5]2[C:21](=[O:46])[CH:22]([NH:23][C:24](=[O:45])[CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:32][C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][CH3:42])[C:37](=[O:43])[C:36]3=[O:44])=[O:34])[C@H:4]2[C:3]1=[O:47]
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)OCc4ccc5ccccc5c4)=C(C)C(=O)[C@H]23)c2ccccc2)C(=O)C1=O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)OCc4ccc5ccccc5c4)C(C)C(=O)[C@H]23)c2ccccc2)C(=O)C1=O
Reaction time: 1 h
Yield: 16 %

Procedure:
The 2-naphthylmethyl 2-methyl-1-oxo-6-[2-phenyl-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]carbapen-2-em-3-carboxylate of Example 31 was taken up in a minimum of tetrahydrofuran, and added to a slurry of activated zinc (2.37 g.) in 5 ml. of acetic acid-30% tetrahydrofuran at 0° C. After 1 hour at 0° C., product was isolated according to procedures detailed in Example 2. The resulting product was taken up in ether, insolubles removed by filtration, and the filtrate evaporated to dryness in vacuo to yield 2-naphthylmethyl 2-methyl-1-oxo-6-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]carbapenam-3-carboxylate [36 mg., 16%; Rf 0.48 (ethyl acetate)].