Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH2:16][CH2:15]3)[C:11]=2F)[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2].[CH3:38][O-:39].[Na+]>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:27][CH:28]=4)(=[O:22])=[O:21])[CH2:16][CH2:15]3)[C:11]=2[O:39][CH3:38])[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(S(=O)(=O)c4ccc(NC(C)=O)cc4)CC3)c(F)c21
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(S(=O)(=O)c4ccc(NC(C)=O)cc4)CC3)c(OC)c21
Yield: 90.6 %

Procedure:
2.16 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[4-(4-acetamidobenzenesulfonyl)-1-piperazinyl]-3-quinolinecarboxylic acid obtained in Example 1 is dissolved in 100 ml of dimethylformamide (DMF). To this is added 7.72 g of 28% sodium methylate and the mixture is refluxed for 2 hours while heating. Then, the reaction mixture is concentrated under reduced pressure. To the residue is added water to dissolve and the solution is neutralized with 2N hydrochloric acid. The precipitated crystals are collected by filtration to give 2.0 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(4-acetamidobenzenesulfonyl)-1-piperazinyl]-8-methoxy-3-quinolinecarboxylic acid. This is suspended in 2N sodium hydroxide solution, and the suspension is refluxed for 2 hours while stirring. The reaction mixture is adjusted to pH 7.0 with acetic acid. The precipitated crystals are collected by filtration and washed with water to give 1.22 g of the titled compound. Melting point: 145° C. (decomp.)
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH:12]=[CH2:13])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:14][CH3:15]>O>[I-:14].[CH3:15][N+:9]1[C:10]([CH:12]=[CH2:13])=[CH:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: CI
Reactant: C=Cc1cn(-c2ccccc2)nn1
Solvent: O
Product: C=Cc1cn(-c2ccccc2)n[n+]1C
Product: [I-]
Reaction time: 8 h

Procedure:
1-phenyl-4-vinyl-1H-1,2,3-triazole (0.9 g, 5.26 mmol) and iodomethane (37.3 g, 263 mmol) were mixed and stirred overnight. Water was added and the salt was extracted in water. The water was removed under vacuum and the precipitate was washed with acetone and the acetone was decanted yielding pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([OH:11])=[O:10])[CH:3]=1.OS(O)(=O)=O.[CH3:17]O>>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:17])=[O:10])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1c[nH]c(=O)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1c[nH]c(=O)c(Cl)c1

Procedure:
A mixture of commercially available 5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (4.000 g; 23.04 mmol) and concentrated H2SO4 (0.3 ml) in anh. MeOH (52 ml) was refluxed, under nitrogen, for 19 h. MeOH was removed under reduced pressure, and the residue was basified by addition of a solution of 10% aq. NaHCO3. The mixture was then extracted with DCM (5×), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording methyl 5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate as a pale yellow solid. LC-MS (conditions D): tR=0.61 min.; [M+H]+: 187.93 g/mol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20]Cl)=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20][N:5]2[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]2=[O:9])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=[N+]([O-])c1ccc(SCCl)cc1
Agent: Cl
Product: O=c1ncc(Cl)cn1CSc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from 5-chloropyrimidin-2-one hydrochloride (10 mmol) and 4-nitro-1-(chloromethylthio)benzene (10 mmol) in a manner similar to that described in Example 2. The reaction time was 31/2 h. Yield: 1.79 g (60%) of the N- and O-isomers in the ratio 5:2. The O-isomer was extracted from the mixture with chloroform, and the remaining N-isomer, the title compound, was recrystallized from MeOH/HOAc; m.p. 165° C. (Found C44.64; H3.03. Calc. for C11H8ClN3O3S: C44.37; H2.71) 1H NMR (DMSO-d6): δ 5.50 (CH2), 7.4-8.3 (Ph), 8.51 (H-4 and H-6, s). IR (KBr): 1660 cm-1 (CO). MS [70 eV, m/z (% rel. int.)]: 297/299 (5/2,M), 143/145 (100/31).
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[N:20]=[C:19]([CH2:21]O)[CH:18]=[CH:17][C:16]=3[CH3:23])=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[CH3:40][S:41]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:43])=[O:42].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1([F:27])[CH2:4][CH:3]1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:16]([CH3:23])=[CH:17][CH:18]=[C:19]([CH2:21][N:47]4[CH2:48][CH2:49][N:44]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:45][CH2:46]4)[N:20]=3)=[CH:14][C:9]=2[N:8]([CH3:24])[S:7]1(=[O:26])=[O:25]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1ccc(CO)nc1-c1ccc2c(c1)N(C)S(=O)(=O)N2CC1CC1(F)F
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1ccc(CN2CCN(S(C)(=O)=O)CC2)nc1-c1ccc2c(c1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
(6-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro-2,1,3-benzothiadiazol-5-yl}-5-methylpyridin-2-yl)methanol (26-6) (25 mg, 0.06 mmol, 1 eq) was dissolved in NMP (0.5 mL) and triethylamine (0.03 mL, 0.18 mmol, 3.0 eq) was added followed by mesyl chloride (0.01 mL, 0.12 mmol, 2.0 eq). After 10 minutes, 1-(methylsulfonyl)piperazine (20.8 mg, 0.13 mmol, 2.0 eq) and DIPEA (0.033 mL, 0.19 mmol, 3.0 eq) were added. The resulting mixture stirred at 80° C. for 10 minutes. The mixture was cooled and purified by reverse phase chromatography (Waters Sunfire MSC18, 15-65% acetonitrile in water with 0.1% TFA modifier) to afford 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-(3-methyl-6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyridin-2-yl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (26-7) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=7.6 Hz, 1 H); 7.48 (d, J=7.6 Hz, 1 H); 7.25 (dd, J=1.6, 8.4 Hz, 1 H); 7.19 (s, 1 H); 7.13 (d, J=8.0 Hz, 1 H); 4.53 (s, 2 H); 3.97 (d, J=7.2 Hz, 2 H); 3.56 (m, 4 H); 3.49 (m, 4 H); 3.33 (s, 3 H); 2.95 (s, 3 H); 2.43 (s, 3 H); 2.21 (m, 1 H); 1.64 (m, 1 H); 1.42 (m, 1H). HRMS m/z (M+H) 542.1693 found, 542.1702 required.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:14][CH:13]=1
Reactant: N#Cc1cccnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc(CNc2ncccc2C#N)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 33.4 %

Procedure:
To a stirred mixture of 2-chloro-nicotinonitrile (Aldrich, 2.20 g, 15.88 mmol) and 4-methoxy-benzylamine (2.27 ml, 17.49 mmol) in 2-propanol (20 ml) was added N,N-diisopropylethylamine (5.53 ml, 31.75 mmol). The reaction mixture was heated to 80° C. and stirred at this temperature for 24 hours. More 4-methoxybenzylamine (0.50 ml, 3.85 mmol) was added and stirring continued at 70° C. for 48 hours. The mixture was cooled to room temperature and the resulting solid material (4-methoxy-benzylamine hydrochloride) removed by filtration. On standing a crystalline product formed in the filtrate, which was isolated by filtration, washed with 2-propanol and dried under reduced pressure affording the title compound as pale yellow crystals (1.27 g). 1H-NMR (DMSO-d6) δ 8.21-8.30 (m, 1H), 7.90 (d, 1H), 7.65 (t, 1H), 7.25 (d, 2H), 6.85 (d, 2H), 6.59-6.68 (m, 1H), 4.50 (d, 2H), 3.75 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[C:5]=1[C:6]([O:8]C)=O.[N+:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[C-]>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:8])[NH:16][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14]2
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: COC(=O)c1c(Cl)cccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccc(Cl)c2c(=O)[nH]1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
To a solution of NaH (652.8 mg, 16.32 mmol) in DMF (20 mL) was added methyl 2-chloro-6-formylbenzoate (2.7 g, 13.6 mmol) and ethyl 2-isocyanoacetate (1.55 g, 13.6 mmol) in DMF (5 mL) at 40° C. over a 20 minute period. The reaction mixture was stirred at 20° C. for an additional 30 minutes. The reaction mixture was subsequently diluted with EtOAc (100 mL) and washed with saturated aqueous Na2CO3. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0-90%) and PE to give the title compound (0.5 g, 15.6%). ESI-MS m/z [M+H]+ 252.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].S([O-])(OC)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Product: COc1cc([N+](=O)[O-])ccc1F

Procedure:
An intimate mixture of 2.0 grams of 2-fluoro-5-nitrophenol, 2.0 grams of potassium carbonate, and 1.0 ml. of methyl sulphate, is heated on the steam bath for 5 minutes and then steam distilled, the volume of liquid in the flask being kept as small as possible. The 2-fluoro-5nitroanisole passes over, and a further quantity is obtained by adding more potassium carbonate (1 gram) and methyl sulphate (0.5 ml.) to the residual liquor, which is then warmed and steam distilled. The 2-fluoro-5-nitroanisole is then recrystallized from hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH:22]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24][CH2:23]1.[S].C(O)(=O)C>C(O)C>[CH:22]1([C:26]2[N:31]=[C:30]([C:32]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]6[CH2:21][CH2:20][CH2:19][CH2:18]6)=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:29]=[CH:28][N:27]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: O=Cc1ccnc(C2CCC2)n1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: [S]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CCC5)n4)[nH]c3n2)C1)N1CCCC1
Reaction time: 16 h

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (135.9 mg, 0.5 mmol) in ethanol was added 2-cyclobutylpyrimidine-4-carbaldehyde (76.2 mg, 0.5 mmol), sulfur (30.1 mg, 0.9 mmol) and acetic acid (0.15 mL) at room temperature under nitrogen. The reaction mixture was stirred for 16 h at reflux. The solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound as a yellow solid. MS (ES+APCI) (M+H) 432.1; LCMS retention time 2.567 min (Method G).
Reaction SMILES: Cl.C([O:4][C:5](=[O:8])[CH2:6][NH2:7])C.Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:39][C:40]1[N:41]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]([CH:60]3[CH2:62][CH2:61]3)=[CH:52][CH:51]=2)[C:42]([S:45][CH2:46][C:47](O)=[O:48])=[N:43][N:44]=1>ClCCl>[Br:39][C:40]1[N:41]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]([CH:60]3[CH2:62][CH2:61]3)=[CH:52][CH:51]=2)[C:42]([S:45][CH2:46][C:47]([NH:7][CH2:6][C:5]([OH:4])=[O:8])=[O:48])=[N:43][N:44]=1
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C(O)CNC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Glycine ethyl ester hydrochloride (0.21 g, 1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 1.86 mmol), 1-hydroxy-7-azabenzotriazole (0.25 g, 1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71 mmol, 3.0) are added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL), and the mixture is stirred at room temperature for 18 hours. Purification by SGC (0-100% EtOAc/Hexanes) affords 2-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)acetic acid.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)(=O)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[ClH:22].[CH3:2][C:1]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]2=[CH:5][N:4]=1
Reactant: CC(=O)NCc1ncccc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ncc2c(OCc3ccccc3)cccn12
Product: Cl
Temperature: 25 °C

Procedure:
Heat under reflux for 0.5 hours a mixture of 5 gms of the compound produced in Example 3 and 75 ml phosphorous oxychloride. Cool the reaction mixture to room temperature and remove the phosphorous oxychloride under reduced pressure. Partition the residue between chloroform and an aqueous solution of sodium bicarbonate. Separate the chloroform layer and dry over potassium carbonate. Filter the resulting dry solution and remove the chloroform from the filtrate under reduced pressure. Chromatograph the residue on silica gel using ethyl acetate-chloroform. Combine the fractions containing the desired product, 3-methyl-8-(phenylmethoxy)imidazo[1,5-a]pyridine and remove the solvent under reduced pressure. Dissolve the resulting solid in absolute ethanol and add an ethanolic hydrogen chloride solution. Remove the ethanol under reduced pressure and recrystallize the residue from acetonitrile to obtain 3-methyl-8-(phenylmethoxy)imidazo[1,5-a]pyridine hydrochloride, mp 174°-175°.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[NH:7][C:6]1=[O:16])[C:2]#[C:3][CH3:4].CI.[C:19](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2[Cl:14])[N:7]([CH3:19])[C:6]1=[O:16])[C:2]#[C:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC#CCn1c(=O)[nH]c2nc(Cl)nc(Cl)c21
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CC#CCn1c(=O)n(C)c2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
7-(2-Butynyl)-2,6-dichloro-7,9-dihydropurin-8-one (435 mg) was dissolved in N,N-dimethylformamide (10 mL), and then methyl iodide (158 μL) and anhydrous potassium carbonate (468 mg) were added to the solution. This reaction solution was stirred at room temperature for 12 hours, and then water (50 mL) was added. After stirring at room temperature for one hour, a white precipitate was collected by filtration. The white solid obtained was washed with water and t-butyl methyl ether to give the title compound (355 mg).
Reaction SMILES: [CH3:1][C@:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]2[C:6]3=[C:7]([C@:15]([CH3:24])([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:16][CH2:17][N:5]3[CH2:4][CH2:3]1)[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2.C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>ClCCl>[CH3:1][C@:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]2[C:6]3=[C:7]([C@:15]([CH3:24])([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:16][CH2:17][N:5]3[CH2:4][CH2:3]1)[CH:8]=[C:9]([NH:12][C:39](=[O:40])[O:41][CH3:42])[CH:10]=2
Reactant: COC(=O)Cl
Reactant: C[C@@]1(c2ccccc2)CCN2CC[C@@](C)(c3ccccc3)c3cc([N+](=O)[O-])cc1c32
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1cc2c3c(c1)[C@](C)(c1ccccc1)CCN3CC[C@@]2(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (1S,7S)-1,7-dimethyl-9-nitro-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline (7), (115 mg, 0.31 mmol), in dicloromethane (15 mL) was added three equivalent of triethyl amine (0.129 mL, 0.93 mmol), followed by methyl chloroformate (0.031 mL, 0.406 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give methyl (1S,7S)-1,7-dimethyl-1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-ylcarbamate (829), (69 mg 52%). 1H NMR (300 MHz, Acetone-d6) ppm 1.72 (s, 6H) 1.89-2.03 (m, 2H) 2.17-2.30 (m, 2H) 2.73-2.88 (m, 2H) 2.92-3.03 (m, 2H) 3.56 (s, 3H) 7.05-7.33 (m, 12H) 8.02 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1>ClCCl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:24](=[O:25])[C:21]2[CH:22]=[CH:23][C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][CH:20]=2)=[N:6][CH:7]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-amino-benzamide (0.247 g, 1 mmol) in dichloromethane (10 mL) and pyridine (0.5 mL) was added a solution of 4-biphenylcarbonyl chloride (0.217 g, 1 mmol) in dichloromethane (5 mL). After stirring overnight the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (25 mL). Separate the layers and wash the organic layer with water (2×10 mL), saturated sodium bicarbonate (2×20 mL), hydrochloric acid (0.2 N, 1×20 mL). Dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified by RPHPLC (30% ethyl acetate/hexane) to give 0.4 g (94%) of pure product.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:13](O)(=[O:16])[CH2:14][CH3:15].CCN=C=NCCCN(C)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: CCC(=O)O
Reactant: NC1CCCc2c(Br)cncc21
Agent: CCN=C=NCCCN(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)NC1CCCc2c(Br)cncc21
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a stirred black solution of (rac)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (317 mg, 1.4 mmol) and propionic acid (115 μL, 1.54 mmol) in CH2Cl2 (7.0 mL) at 0° C. was added EDCI (295 mg, 1.54 mmol), stirring was continued over night and the reaction mixture was allowed to warm up to RT. The reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. 10% KH2PO4, aq. sat. NaHCO3 and with aq. sat. NaCl solution. The combined organic phases were dried over Na2SO4, filtered, evaporated and purified by precipitation CH2Cl2/n-pentane to afford the title compound (365 mg, 92%) as light brown solid. MS: 283.0 (M+H+, 1 Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]1[CH2:31][C:32](O)=[O:33].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH:23]1[CH2:31][C:32]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:33]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)CC1Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CC1Cc2ccccc2C1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 77.1 %

Procedure:
Preparation of example 121 from the title compound of Example 7 (hydrochloride) (41 mg, 0.131 mmol), indan-2-yl-acetic acid (28 mg, 0.157 mmol), triethylamine (0.055 mL, 0.393 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (60 mg, 0.157 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. When the reaction was judged complete, the mixture was filtered to collect the solids, which were then washed with methanol. After drying under vacuum, the title compound (45 mg, 0.101 mmol) was obtained as a yellow powder in 77% yield.
Reaction SMILES: Br[C:2]([F:6])=[C:3]([F:5])[F:4].Cl[Si:8]([CH3:19])([CH3:18])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1.C([Li])(CC)C.C1CCCCC1.Cl>CCOCC>[F:6][C:2]([Si:8]([CH3:18])([CH3:19])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=1)=[C:3]([F:5])[F:4]
Reactant: FC(F)=C(F)Br
Reactant: CCOc1ccc([Si](C)(C)Cl)cc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCOc1ccc([Si](C)(C)C(F)=C(F)F)cc1
Temperature: -65 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
A -30° C. solution of bromotrifluoroethylene (7.15 g, 0.044 mol) in ether is treated with p-(chlorodimethylsilyl)phenetole (9.54 g, 0.044 mol), cooled to -65° C., treated dropwise with a 1.3M solution of sec-butyllithium in cyclohexane (34.2 mL, 0.044 mol) while maintaining the temperature below -60° C., stirred at -65° C. for 5 hours, stirred at room temperature overnight, cooled to 0° C., treated with dilute hydrochloric acid, and diluted with ether. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue which is distilled to give the title product as a clear liquid (7.66 g, bp 84°-92° C./0.8 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1.C(Cl)Cl.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>C(N(CC)CC)C>[CH3:22][S:23]([O:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][CH2:13]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-[4-(2-methoxyphenyl)piperazin-1-yl]-1-propanol (24 g, 95.87 mmol), prepared as in Example 10, in 25 mL of triethylamine and 300 mL of methylene chloride was cooled to approximately 0° C. and then methanesulfonyl chloride (8.8 mL) was added dropwise. The mixture was stirred at approximately 0° C. for 1 hour and then at room temperature for 0.5 hours. The mixture was poured into saturated sodium carbonate and stirred for 15 minutes. The organic phase was separated, washed with saturated sodium carbonate (2×150 mL), dried (MgSO4) and concentrated to give 3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl methanesulfonate (21 g, 63.63 mmol).