Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH:7]([NH:13][S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][CH:7]([NH:13][S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:8]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)CC(NS(=O)(=O)N1CCOCC1)CN2
Product: N#Cc1ccc2c(c1)CC(NS(=O)(=O)N1CCOCC1)CN2Cc1cccc(Cl)c1

Procedure:
The title compound was prepared from 156A and 3-chlorobenzaldehyde by procedures analogous to those described in Example 22A. HPLC: 99% at 6.7 min(retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 447 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:23])[CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)[OH:12])=[CH:4][CH:3]=1
Reactant: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(O)CCC(O)c2ccc(Br)cc2)ccc1Cl
Temperature: 25 °C

Procedure:
The product from Example 191A (4.62 g, 11.65 mmole) was mixed with EtOH (100 mL) and the resulting slurry was treated in portions over a five minute period with solid NaBH4 (0.97 g, 25.6 mmole). The resulting foaming slurry was stirred and heated at reflux for 1 hr. The reaction was deemed complete by LC-MS. The reaction mixture was cooled to room temperature and concentrated in vacuo to an oily residue. The residue was dissolved in CH2Cl2 and applied to an 80 g silica gel column. The column was eluted with a gradient of hexane/acetone, 90/10 to 20/80 over 32 minutes. The fractions containing product were pooled and concentrated in vacuo giving the title compound as a white solid, 3.14 g, 67%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:17])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])[CH:5]=[CH:6][CH:7]=1.C[Li].C([Li])(C)(C)C.[B:25](OC)([O:28]C)[O:26]C>O1CCCC1.CCCCC>[CH3:17][N:8]([C:4]1[CH:3]=[C:2]([B:25]([OH:28])[OH:26])[CH:7]=[CH:6][CH:5]=1)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10]
Reactant: CCCCCNC(=O)N(C)c1cccc(Br)c1
Reactant: COB(OC)OC
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCNC(=O)N(C)c1cccc(B(O)O)c1
Yield: 39 %

Procedure:
In a manner similar to that of Example (18a), by reaction of 123 g (0.411 mol, 1 eq) of 1-(3-bromophenyl)-1-methyl-3-pentylurea in 1.23 L of tetrahydrofuran, 150 mL (0.452 mol, 1.1 eq) of methyllithium, 530 mL (0.904 mol, 2.2 eq) of a 1.7 M solution of tert-butyllithium in pentane and 115 mL (0.904 mol, 2.2 eq) of trimethyl borate, and after purification by chromatography on silica gel (50/50 heptane/ethyl acetate) and crystallization from ethyl acetate/heptane, 42.0 g of 3-(1-methyl-3-pentylureido)phenylboronic acid are obtained in the form of a pink-colored powder. Yield=39%
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[O:40]=[C:20]1[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]#[N:10]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: N#Cc1cccc(CBr)c1
Agent: BrCC1CCCCO1
Product: N#Cc1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using α-bromo-m-tolunitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1H)-one, 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile was obtained (66%) as a colorless solid: mp 173-178° C. (ethyl acetate/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.60-7.63 (m, 3H), 7.44-7.47 (m, 1H), 7.21-7.24 (m, 2H), 7.05 (t, J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.93-4.97 (m, 3H), 4.66-4.69 (m, 1H), 4.13-4.17 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7, 155.3, 144.8, 141.5, 138.4, 137.4, 132.1, 131.8, 131.7, 130.9, 129.9, 129.0, 124.3, 123.9, 120.7, 118.4, 113.1, 111.4, 108.8, 99.5, 80.1, 64.5, 63.9, 58.0, 43.4; MS (ES+) m/z 410.8 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)[CH:8]=[CH:7][C:6]=1[Cl:19])C.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[Cl:19][C:6]1[CH:7]=[CH:8][C:9]([C:11]2[CH:15]=[C:14]([CH:16]3[CH2:17][CH2:18]3)[NH:13][N:12]=2)=[CH:10][C:5]=1[C:4]([OH:20])=[O:3]
Reactant: CCOC(=O)c1cc(-c2cc(C3CC3)[nH]n2)ccc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-c2cc(C3CC3)[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 134.4 %

Procedure:
To a solution of 2-chloro-5-(5-cyclopropyl-1H-pyrazol-3-yl)-benzoic acid ethyl ester (0.05 g, 0.17 mmol) in methanol (4 mL) was added KOH (0.12 g). The mixture was shaken at room temperature for 16 h. The mixture was acidified with 10% aqueous citric acid and extracted with ethyl acetate. The combined organic layers were washed with water and brine, and concentrated in vacuo to afford the title compound (0.06 g).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.O=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:26]([O:25][C:23]([CH2:22][N:5]1[CH2:6][CH2:7][C:2]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)([CH3:1])[CH2:3][CH2:4]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C=O
Reactant: CC(C)(C)OC(=O)N1CCN(C2(C)CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(C)(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.53 g (4.78 mmol) tert-butyl 4-(4-methyl-piperidin-4-yl)-piperazine-1-carboxylate and 1.1 mL (5.55 mmol) ethyl oxo-acetate (50% in toluene) in 50 mL THF was stirred for 1 h at RT. The reaction mixture was cooled to 0° C., 1.25 g (5.90 mmol) sodium triacetoxyborohydride was added batchwise and after elimination of the cooling bath the mixture was stirred overnight at RT. It was combined with 10 mL 20% NaHCO3 solution, extracted exhaustively with EtOAc and the combined organic phases were dried over Na2SO4. After elimination of the desiccant and solvent the residue was purified by chromatography (Alox, DCM/EtOH 100:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[N:8]([CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28]([OH:30])=O)[CH2:7][CH2:6]2.Cl.CN.C1C[N:43]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:42]C1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=1)[N:8]([CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28]([NH:43][CH3:42])=[O:30])[CH2:7][CH2:6]2
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: COc1cc2c(cc1OC)C(CCc1ccc(C(F)(F)F)nc1)N(C(C(=O)O)c1ccccc1)CC2
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(c1ccccc1)N1CCc2cc(OC)c(OC)cc2C1CCc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of {6,7-dimethoxy-1-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-phenyl-acetic acid (0.20 mmol), methylamine hydrochloride (0.20 mmol), PyBOP (0.20 mmol) and DIPEA (0.46 mmol) in DMF (1.0 mL) is stirred at RT for 20 h. Water and EA are added, the layers are separated and the aqueous layer is extracted with EA. The combined organic extracts are dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (EA) to give the desired product as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH2:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH:9]([CH3:10])[CH2:12][OH:13])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(F)cc1
Reactant: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(CO)C(=O)c1ccc(F)cc1

Procedure:
A mixture of 45.7 g. (0.3 moles) of 4'-fluoropropiophenone, 9 g. (0.3 moles) of paraformaldehyde, 4 g. (0.03 mole) of anhydrous potassium carbonate and 200 ml. of methyl alcohol is stirred at 35°C for two days. The reaction is quenched in water and acidified with hydrochloric acid. The product is extracted into benzene. The benzene layer is washed with water and concentrated in vacuo to give 4'-fluoro-3-hydroxy-2-methylpropiophenone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[S:25][CH2:24]1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1C(=O)C2=CC=CC=[C:13]2[C:12]1=[O:21])=[O:5])[CH3:2].NN.C(Cl)(=O)C>>[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([NH:22][C@@H:23]1[C:29](=[O:30])[N:28]([CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:27]2[CH:39]=[CH:40][CH:41]=[CH:42][C:26]=2[S:25][CH2:24]1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:21])[CH3:13]
Reactant: CCOC(=O)[C@H](CCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: NN
Solvent: CC(=O)Cl
Product: CCOC(=O)[C@H](CCCCNC(C)=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O

Procedure:
A half g of tert-butyl 3(R)-[1(S)-ethoxycarbonyl-5-phthalimidopentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate is treated with hydrazine in a manner similar to that described in Reference Example 44, and then reacted with acetyl chloride to give tert-butyl 3(R)-[5-acetylamino-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (0.25 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13]#[N:14])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=O.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:16]3[CH2:17][CH2:18][CH2:19][N:15]3[C:9]2=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CCCN1
Reactant: N#CCN(C(=O)Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c2n(c(=O)n1-c1ccc(Cl)cc1)CCC2
Temperature: 25 °C

Procedure:
N-(4-chlorophenyl)-N-cyanomethylcarbamoyl chloride, prepared as described in Example 53, (2.7 g, 0.012 mol) was dissolved in 10 mL of dimethylformamide and added dropwise to a cold solution (0° C.) of 2-pyrrolidinone (1.0 g, 0.012 mol) and sodium hydride (0.96 g, 0.024 mol) in 20 mL of DMF. The solution was allowed to warm to ambient temperature over two hours, then it was poured onto ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over magnesium sulfate, and concentrated to yield an oil. Elution of this oil through a silica gel column using 1:2 ethyl acetate:hexane furnished 0.4 g of 2-(4-chlorophenyl)-2,3,6,7-tetrahydro-3-oxo-5H-pyrrolo-[l,2-c]imidazol-1-carbonitrile, as a solid (m.p. 154°-6° C.).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:48]6[CH2:53][CH2:52][O:51][CH2:50][CH2:49]6)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=O)(C)(C)C.Cl.[CH3:61][O:62][C:63]([NH:65][CH:66]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:67]([OH:69])=O)=[O:64].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CO>[CH3:61][O:62][C:63](=[O:64])[NH:65][CH:66]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:67]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:48]6[CH2:53][CH2:52][O:51][CH2:50][CH2:49]6)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:24][CH:25]=2)=[CH:18][N:19]=1)=[O:69]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(F)(F)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of 4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.04 g, 0.05 mmol) in CH2Cl2 (0.5 mL) and MeOH (0.05 mL) was added HCl (in dioxanes, 4 M, 0.3 mL, 1.2 mmol). The solution was stirred at room temperature for 2 h and concentrated to dryness. The solid was slurried with CH2Cl2 (0.5 mL). Methoxycarbonylamino-phenyl-acetic acid (0.02 g, 0.07 mmol) and Potassium Phosphate (0.03 g, 0.14 mmol) were added and the resulting slurry was cooled to 0° C. (external, ice). COMU (0.03 g, 0.06 mmol) was added and the reaction was stirred at room temperature for 2 h. The slurry was diluted with CH2Cl2 and filtered through celite. The filtrate was concentrated and purified by preparative HPLC (Gemini, 15→50% MeCN in H2O (0.1% TFA)) to provide to provide {2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl ester (0.02 g, 49%). LCMS-ESI+: calc'd for C49H50F2N8O7: 900.38 (M+); Found: 901.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:9]2[C:10]3[C:5](=[N:4][CH:3]=[C:2]([Br:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:12])=[CH:18][CH:19]=1
Reactant: O=c1ccc2ncc(Br)cc2[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)ccc3ncc(Br)cc32)cc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a stirred solution of 7-bromo-1,5-naphthyridin-2(1H)-one (C-4) (29 g, 128.9 mmol, 1.0 eq) in DMF (200 mL) was added sodium hydride (60% in mineral oil, 7.73 g, 193.3 mmol, 1.5 eq) in portions at RT, the mixture was stirred at 30 to 40° C. for 1 h. 1-(Chloromethyl)-4-methoxybenzene (30.28 g, 193.3 mmol, 1.5 eq) was added dropwise. The resulting mixture was stirred at 30 to 40° C. overnight and quenched with water (500 mL) and extracted with ethyl acetate (5×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10-50% ethyl acetate/petroether) to afford the desired product, 1-(4-methoxybenzyl)-7-bromo-1,5-naphthyridin-2(1H)-one (C-5) (20.2 g, 45.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.15 (s, 1H), 8.00 (d, J=10 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.02 (d, J=9.6 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 5.45 (s, 2H), 3.71 (s, 3H); ESI-MS m/z: 345.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:10]#[CH:11])[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N)(=[O:20])C.[OH-].[K+]>C(O)(=O)C.C(OC(=O)C)(=O)C.C(Cl)Cl.CO>[OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:10](=[O:20])[CH3:11])[CH2:3][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(N)=O
Reactant: C#CC(O)(CN1CCCCC1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(O)(CN1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 114.5 g (0.5 mole) of 2-hydroxy-2-phenyl-1 piperidino-3-butyne in 500 mL of acetic acid and 50 mL of acetic anhydride is added 160 g (0.5 mole) of mercuric acetate. After being stirred overnight at room temperature, the mixture is poured into a 1-L round bottomed flask equipped with an overhead stirrer and diluted with 500 mL of methylene chloride. To this is added 86 g (1.18 mole) of acetamide and 1 L of celite. After being stirred overnight, the mixture is filtered through a large pad of celite. The filtrate is washed three times with water, twice with a 5% aqueous solution of sodium hydroxide, and once with brine. After the organic layer is dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure The residue is dissolved in a solution of 35 g (0.57 mole) of potassium hydroxide in 750 mL of methanol and heated to reflux for 4 hours; the solution is cooled and then poured onto ice. The mixture is extracted four times with methylene chloride. The organic layers are combined, washed four times with water, once with brine dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. Distillation of the residue gives 2-hydroxy-2-phenyl-1-piperidino-3-butanone.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[N:12]=[C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:10]([C:18]2[CH:23]=[CH:22][C:21](=[O:24])[NH:20][CH:19]=2)=[CH:9][C:6]=1[C:7]#[N:8].I[CH2:26][CH3:27]>CO>[NH2:4][C:5]1[N:12]=[C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:10]([C:18]2[CH:23]=[CH:22][C:21](=[O:24])[N:20]([CH2:26][CH3:27])[CH:19]=2)=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: CCI
Reactant: N#Cc1cc(-c2ccc(=O)[nH]c2)c(-c2ccco2)nc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1cc(-c2cc(C#N)c(N)nc2-c2ccco2)ccc1=O
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
Sodium methoxide (155 mg, 2.87 mmol) was added to a suspension of 2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile (400 mg, 1.44 mmol) in methanol (8 ml) at room temperature in a nitrogen atmosphere, followed by stirring. After 15 minutes, iodoethane (0.35 ml, 4.38 mmol) was added thereto, followed by stirring as it was. After 15 hours, additional iodoethane (0.35 ml, 4.38 mmol) was added thereto, and the mixture was further stirred. After 24 hours, the reaction solution was concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane, hexane:ethyl acetate=2:1, 1:2, 1:5). The resulting crude objective compound was suspended in diethyl ether, and then the solid was collected by filtration and washed with diethyl ether, to give the title compound (149 mg, 34%) as a pale yellow solid.
Reaction SMILES: FC1C(OC)=C2C(=CC=1)NC(C)CC2.C(OC=C(C(OCC)=O)C(OCC)=O)C.[F:30][C:31]1[CH:43]=[C:41]2[C:42]3[N:37]([CH:38]=[C:39]([C:45]([O:47]CC)=[O:46])[C:40]2=[O:44])[CH:36]([CH3:50])[CH2:35][CH2:34][C:33]=3[C:32]=1[O:51][CH3:52]>O.[OH-].[Na+]>[F:30][C:31]1[CH:43]=[C:41]2[C:42]3[N:37]([CH:38]=[C:39]([C:45]([OH:47])=[O:46])[C:40]2=[O:44])[CH:36]([CH3:50])[CH2:35][CH2:34][C:33]=3[C:32]=1[O:51][CH3:52]
Reactant: CCOC(=O)c1cn2c3c(c(OC)c(F)cc3c1=O)CCC2C
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: COc1c(F)ccc2c1CCC(C)N2
Agent: [Na+]
Solvent: O
Product: COc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1CCC3C
Temperature: 140 °C

Procedure:
A mixture of 1.2 g of 6-fluoro-5-methoxy-1,2,3,4-tetrahydroquinaldine and 2.5 g of diethyl ethoxymethylenemalonate was heated at 140° C. for 3 hours, and was then cooled to 100° C. To the crude hot diethyl 2-[N-(6-fluoro-5-methoxy-1,2,3,4-tetrahydroquinaldinyl)]methylenemalonate was added 25 g of polyphosphoric acid, and the mixture was heated on a steam bath for one hour. The mixture containing ethyl 6,7-dihydro-9-fluoro-8-methoxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate was cooled to about 20° C., diluted with an equal volume of water and basified with 50% sodium hydroxide solution. This solution was heated at its reflux temperature for two hours and filtered hot through celite. The filtrate was cooled to about 20° C. and acidified with concentrated hydrochloric acid. The solid was separated by filtration to provide 1.2 g of off-white 6,7-dihydro-9-fluoro-8-methoxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. Recrystallization from aqueous N,N-dimethylformamide provided pure product, m.p. 234°-236° C. Analysis: Calculated for C15H14FNO4 : %C, 61.8; %H, 4.8; %N, 4.8; Found: %C, 61.7; %H, 4.6; %N, 4.8.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:23])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)[CH2:7]1.ClCl>ClCCl>[Cl:1][C:15]1[CH:16]=[C:17]([C:20](=[O:22])[CH3:21])[CH:18]=[CH:19][C:14]=1[CH:8]1[CH2:7][C:6]([CH3:23])([CH3:5])[CH2:11][C:10]([CH3:12])([CH3:13])[CH2:9]1
Reactant: [Cl-]
Reactant: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)cc1
Agent: ClCl
Agent: [Al+3]
Solvent: ClCCl
Product: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
40.25 g of aluminium chloride are added at 0° C., under an inert atmosphere, to 350 ml of dichloromethane, followed by addition of 5 g of 1-[4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone (compound V.1) dissolved in dichloromethane. After stirring for 2 hours at 0° C., 17.1 ml of chlorine gas (d=1.565, measured in the liquid state at −78° C.) are bubbled into the reaction. After warming to room temperature, a water/ice mixture is added to the reaction mixture. The resulting mixture is extracted with dichloromethane, the phases are separated after settling has taken place, and the organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified on a column of silica gel, eluting with a 7/3 (v/v) cyclohexane/dichloromethane mixutre; yield=74%; m.p.=64° C.