Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[CH3:7][O:8][C:9]([C@H:11]1[C@H:16]([CH3:17])[O:15][C@@H:14]([CH3:18])[CH2:13][N:12]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[O:10]>>[CH3:7][O:8][C:9]([C@H:11]1[C@H:16]([CH3:17])[O:15][C@@H:14]([CH3:18])[CH2:13][N:12]1[S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:2][C:3]#[C:4][CH2:5][CH3:6])=[CH:26][CH:27]=1)(=[O:21])=[O:20])=[O:10]
Reactant: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(O)cc1
Reactant: CCC#CCCl
Product: CCC#CCOc1ccc(S(=O)(=O)N2C[C@H](C)O[C@@H](C)[C@@H]2C(=O)OC)cc1

Procedure:
The title compound was prepared in a manner similar to Preparation 3 from 1-chloro-pent-2-yne and (2S,3R,6S)-4-(4-Hydroxy-benzenesulfonyl)-2,6-dimethyl-morpholine-3-carboxylic acid methyl ester. 1HNMR (400 MHz, CDCl3): δ=7.70 (d, J=8.9 Hz, 2H), 7.0 (d, J=8.9 Hz, 2H), 4.71 (bs, 2H), 4.52 (q, J=7.0 Hz, 1H), 4.27 (s, 1H), 3.97 (m, 1H), 3.54 (s, 3H), 2.98 (dd, J=12.1 and 10.8, 1H), 2.21 (m, 2H), 1.44 (d, J=6.9 Hz, 3H), 1.11 (t, J=7.5 Hz, 3H), 1.05 (d, J=6.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][C:16]=2[N+:25]([O-])=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:35]([O:37][CH2:38][C:39](Cl)=O)[CH3:36]>[Pt].C(O)C>[CH2:35]([O:37][CH2:38][C:39]1[N:14]([CH2:13][C:2]2([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:36]
Reactant: CCOC(=O)N1CCC(O)(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Reactant: CCOCC(=O)Cl
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OCC)CC1
Reaction time: 2.5 h
Yield: 60.9 %

Procedure:
A mixture of ethyl 4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate (4.53 g, 12.1 mmol) and 5% platinum on carbon (0.50 g) in ethanol was hydrogenated on a Parr apparatus at 40 psi (2.8×105 Pa) for 2.5 h. The mixture was filtered through CELITE filter agent and the filtrate was concentrated. The residue was concentrated twice from toluene and once from chloroform to remove the ethanol, then was dissolved in dichloromethane (100 mL). To the solution at 0° C. was added triethylamine (1.86 mL, 13.3 mmol) and ethoxyacetyl chloride (88%, 1.77 g, 12.7 mmol). After 1 h at rt, the solution was concentrated to a yellow foam and ethanol (120 mL) and triethylamine (6 mL) were added. The resulting solution was heated at reflux for 16 h and then concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was washed twice with brine, dried over MgSO4, filtered, and concentrated to a crude yellow oil. The oil was purified by flash chromatography (silica gel, gradient elution with 2-7% methanol/dichloromethane) to provide ethyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate as a yellow foam (3.04 g, 61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=O)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[Na+].C(=O)([O-])[O-]>C(OC(=O)C)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])/[CH:5]=[C:15]1\[N:14]=[C:11]([CH3:12])[O:18][C:16]\1=[O:17]
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1ccc(O)c(F)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC1=N/C(=C\c2ccc(O)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 85 %

Procedure:
Commercially available 3-fluoro-4-hydroxybenzaldehyde (14 g, 0.1 mol), N-acetylglycine (14 g, 0.12 mol), sodium carbonate (10.6 g, 0.1 mol) and sodium acetate (16.6 g, 0.2 mol) were mixed at r.t. in 60 mL of acetic anhydride and stirred at moderate heating until full dissolution of carbonate. Then the mixture was refluxed for 2 hours, cooled down to r.t. and diluted with water (200 mL). The precipitate was filtered and used without further purification: 22.34 g. (Yield ˜85%)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>N1C=CC=CC=1.N1CCCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 2 chloro-5-nitrobenzaldehyde (100 g., 0.54 mole), malonic acid (122 g., 1.2 mole) in pyridine (300 ml) and piperidine (5 ml) was heated at 100° C. for one hour, during which time considerable gassing occurred. After refluxing the reaction mixture for a further few minutes, it was then cooled. The resulting precipitate was collected, washed with water and dried to give an 80% yield, m.p. 226°-228° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[Cl:19].[Li]CCCC.[CH3:25][C:26]1[S:27][C:28]([C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[C:29]([CH3:31])[N:30]=1.C(=O)=O.CC(C)=O>C1COCC1>[Cl:12][C:7]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([Cl:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:32]([C:28]3[S:27][C:26]([CH3:25])=[N:30][C:29]=3[CH3:31])([OH:36])[CH:33]([CH3:35])[CH3:34])[CH:3]=2)[N:8]=1
Reactant: Cc1nc(C)c(C(=O)C(C)C)s1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1-c1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1nc(C)c(C(O)(c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)C(C)C)s1
Temperature: -75 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-2,4-dichloro-3-phenylquinoline (275 mg, 0.78 mmol, Intermediate 1: step c) was added THF (10 mL) to give a homogeneous clear solution. The solution was cooled in a dry ice—acetone bath and n-BuLi (2.5 M in hexanes, 0.28 mL, 0.7 mmol) was added which resulted in an immediate orange-brown homogeneous solution. After 2 minutes, a solution of 1-(2,4-dimethylthiazol-5-yl)-2-methylpropan-1-one (200 mg, 1.09 mmol, Intermediate 4: step b) in 3 mL THF was added. The reaction mixture was maintained at −75° C. for 5 minutes then the dry ice—acetone bath was replaced with a 0° C. ice-bath. After 20 minutes the ice-bath was removed and the mixture was stirred at room temperature for 20 minutes. The mixture was quenched after a total reaction time of 45 minutes with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (100% DCM increasing to 20% EtOAc/DCM) provided the title compound as a white amorphous solid. 1H NMR (500 MHz, CD2Cl2) δ 8.42 (d, J=1.9 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.9, 2.1 Hz, 1H), 7.57-7.46 (m, 3H), 7.41-7.27 (m, 2H), 2.77 (p, J=6.6 Hz, 1H), 2.52 (s, 3H), 2.19 (s, 3H), 1.16 (d, J=6.7 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H); MS (ESI): mass calcd. for C24H22Cl2N2OS, 456.1, m/z found 457.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[O:7])=[CH:4][C:3]=1[C:19]1[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=1.[H-].[Na+].Br[CH2:30][O:31][C:32](=[O:34])[CH3:33].CO>CN(C=O)C>[CH3:30][O:31][C:32](=[O:34])[CH2:33][N:8]([C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[C:3]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=2)[CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1NC(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1
Reactant: CC(=O)OCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CN(C(=O)c1ccc(Cl)c(-c2ncc(Cl)cc2Cl)c1)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To 4-chloro-3-(3,5-dichloro-pyridin-2-yl)-N-(2-methoxy-phenyl)-benzamide (40 mg, 0.1 mmol) in DMF (0.6 mL) at 0-5° C., NaH (8 mg, 0.2 mmol, 60% in mineral oil) was added and the mixture was stirred for 25 min at rt. Upon addition of bromomethylacetate (21 μL, 0.2 mmol), the mixture was stirred at room temperature for 12 hrs. Addition of MeOH (0.3 mL) was followed by filtration and purification on preparative HPLC to afford [[4-chloro-3-(3,5-dichloro-pyridin-2-yl)-benzoyl]-(2-methoxy-phenyl)-amino]-acetic acid methyl ester 17-1.
Reaction SMILES: C([O:4][CH2:5][C@@:6]([NH:19]C(=O)C)([CH3:18])[CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16]Br)=[CH:12][CH:13]=1)(=O)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([OH:33])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].N[C@](C)(CCC1OC(C#CCOC2C=CC(Cl)=CC=2)=CC=1)CO>>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[NH2:19][C@:6]([CH3:18])([CH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]#[C:15][CH2:16][O:33][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: CC(=O)N[C@](C)(CCc1ccc(C#CCBr)o1)COC(C)=O
Reactant: COc1ccc(O)cc1OC
Agent: C[C@](N)(CO)CCc1ccc(C#CCOc2ccc(Cl)cc2)o1
Agent: O=C(O)C(=O)O
Product: COc1ccc(OCC#Cc2ccc(CC[C@@](C)(N)CO)o2)cc1OC
Yield: 68 %

Procedure:
The title compound was synthesized in a yield of 68% using (2R)-1-acetoxy-2-acetylamino-2-methyl-4-[5-(3-bromoprop-1-ynyl)furan-2-yl]butane obtained in Example (22b) and 3,4-dimethoxyphenol as the starting materials by conducting successively the reactions similar to those mentioned in Examples (22c) and (22d).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].Cl.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.[NH:24]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@@H:25]([C:41]([OH:43])=O)[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].NCC(N)=O>CN(C=O)C>[NH:24]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@@H:25]([C:41]([NH:1][CH2:2][C:3]([NH2:5])=[O:4])=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32]
Reactant: NCC(N)=O
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Reaction time: 8 h
Yield: 71 %

Procedure:
GlyNH2.HCl (2.65 g, 0.024 mol) is dispersed in DMF and to this is added Et3N (3.35 ml, 0.024 mol) and HOBT (3.7 g, 0.024 mol). 9.0 g (0.024 mol) of BOC-D-Lys(Z) in a large volume of DMF is added and the GlyNH2 goes into solution. The total volume of DMF is 400 ml. The reaction is stirred overnight and then filtered. The solvent is evaporated off and the residue dissolved in CH2Cl2. This is washed with citric acid solution, Na2CO3 solution and then NaCl solution, and dried with MgSO4. The mixture is filtered, the filtrate evaporated down and the residue is taken up in ethyl acetate and cooled. The solid is filtered and washed with pet ether. More solid is obtained from the filtrate. Both crops are combined and triturated with ether. 7.5 g of a tan, solid is obtained in a 71% yield:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]([C:10]([F:13])([F:12])[F:11])[C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:22]([N:24]=C=O)=[O:23].N>O1CCCC1.CO>[NH2:24][C:22]([NH:1][C:2]1[S:3][C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]([C:10]([F:11])([F:13])[F:12])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:23]
Reactant: NC(=O)c1c(N)sc(-c2ccccc2)c1C(F)(F)F
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)Nc1sc(-c2ccccc2)c(C(F)(F)F)c1C(N)=O
Reaction time: 0.08 h
Yield: 36.1 %

Procedure:
2-Amino-4-trifluoromethyl-5-phenyl-3-thiophenecarboxamide (0.35 g) was suspended in tetrahydrofuran (10 ml) and trichloroacetylisocyanate (0.19 g) was added dropwise with stirring over 5 minutes. Stirring was continued for 1 h at room temperature and then a 2M solution of ammonia in methanol (10 ml) was added and stirring continued for a further 12 h. A precipitate formed and was filtered off and washed with ethyl acetate (5 ml) to give the title urea (0.12 g).
Reaction SMILES: [Cl:1][CH:2]([C:7](=[O:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].C(Cl)Cl.P>[Ru].CO>[Cl:1][CH:2]([C@H:7]([OH:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCC(=O)C(Cl)C(=O)OC
Agent: [Ru]
Agent: P
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H](O)C(Cl)C(=O)OC
Yield: 95 %

Procedure:
In a 100 ml Hastelloy-made autoclave having been purged with nitrogen were put 10 g (0.0607 mol) of the methyl 2-chloro-3-oxopentanoate prepared in (1) above, 0.2 ml of a methylene chloride solution of 26 mg (0.144 mmol) of a ruthenium-optically active phosphine complex Ru2Cl4 [(+)-Tol-BINAP]2NEt3, and 30 ml of methanol, and the mixture was allowed to react at 50° C. under a hydrogen pressure of 30 atm for 18 hours. Methanol was removed by evaporation to give 9.61 g (0.0577 mol; yield: 95.0%) of the title compound. Optical rotation [α]D25 =+6.35° (c=0.976, CHCl3)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:30][C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37](Cl)=[O:38])=[CH:33][CH:32]=1>CN(C=O)C>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:37](=[O:38])[CH2:36][O:35][C:34]3[CH:40]=[CH:41][C:31]([Cl:30])=[CH:32][CH:33]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (40 mg, 0.12 mmol) and pyridine (15 μl, 0.18 mmol) in DMF (1 ml) was added 4-chlorophenoxyacetyl chloride (27 mg, 0.13 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, brine and was dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (32 mg, 53%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[S:18][CH:19]=3)=[CH:11][CH:10]=2)O1.Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[S:44][C:43]([C@@H:45]3[CH2:49][CH2:48][CH2:47][N:46]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:42][CH:41]=2)=[CH:36][CH:35]=1.CC1(C)C(C)(C)OB(C2C=CC(C3SC([C@@H]4CCCN4C(OC(C)(C)C)=O)=NC=3)=CC=2)O1>>[C:28]([O:27][C:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[C:17]1[S:18][CH:19]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[S:44][C:43]([C@@H:45]5[CH2:49][CH2:48][CH2:47][N:46]5[C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])=[N:42][CH:41]=4)=[CH:36][CH:35]=3)=[CH:10][CH:11]=2)[N:16]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)s1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cs1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)s1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)s4)cc3)cc2)cs1

Procedure:
Compound 43a was prepared in the same manner as described in Example 4 except that Compounds 13a and 21a, instead of Compounds 2a and 3a, were used.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.O=[C:26]1[CH2:30][CH2:29][CH:28]([C:31]([O:33]C)=[O:32])[CH2:27]1.O>C1(C)C=CC=CC=1>[C:31]([CH:28]1[CH2:29][CH2:30][C:26]2([O:6][CH2:5][C:2]([CH3:7])([CH3:1])[CH2:3][O:4]2)[CH2:27]1)([OH:33])=[O:32]
Reactant: CC(C)(CO)CO
Reactant: COC(=O)C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC2(CCC(C(=O)O)C2)OC1

Procedure:
72.8 g (0.70 mole) of 2,2-dimethylpropane-1,3-diol and 12.2 g (0.05 mole) of pyridinium-4-toluenesulphonate are added one after another to 40.0 g (0.28 mole) of methyl 3-oxocyclopentane carboxylate OCCME in 560 ml of absolute toluene. The mixture is boiled for 1.5 hours in a water separator; after 30 minutes the solid is dissolved. Approximately 8 ml of H2O in total are separated out. After cooling, the solution is washed three times using 100 ml of H2O each time, the toluene phase is dried over MgSO4 and evaporated in vacuo. The oily residue is fractionally distilled in vacuo at 0.6 mbar over a metallised pin tube column 20 cm long.
Reaction SMILES: [NH:1]([C:8]1([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].II>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][C:19]=1[CH2:18][N:11]1[CH2:10][CH2:9][C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]1
Reactant: ClCC1=Cc2ccccc2CC1
Reactant: NC(=O)C1(Nc2ccccc2)CCNCC1
Agent: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NC(=O)C1(Nc2ccccc2)CCN(CC2=Cc3ccccc3CC2)CC1

Procedure:
A mixture of 4-anilino isonipecotamide (5.5 g), 3,4-dihydro-2-chloromethylnaphthalene (4.0 g), and powdered sodium carbonate (3.5 g) in toluene (200 ml) containing several crystals of iodine is refluxed for 14 hours with vigorous stirring under nitrogen. The reaction mixture is then cooled, diluted with methylene chloride (100 ml), and filtered. The filtrate is concentrated and the crude product triturated with ethyl acetate (100 ml) to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:34](=O)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (4.00 g, 9.1 mmol) in anhydrous DCE (60 mL) were added hexanal (Aldrich, 1.80 mL, 14.6 mmol) and sodium triacetoxyborohydride (6.17 g, 29.1 mmol). The resulting mixture was stirred at 70° C. overnight. Then the reaction mixture was poured into water (60 mL) and extracted with DCM (2×60 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give a yellow oil. Purification by flash chromatography on silicagel (c-Hex/EtOAc (9/1)) gave 4.41 g (92%) of the title compound as a yellow oil. HPLC, Rt: 6.2 min (purity: 100%). LC/MS, M+(ESI): 524.1. 1H NMR (CDCl3) δ: 7.48 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.25 (d, J=3.0 Hz, 1H), 7.20 (d, J=8.3 Hz, 2H), 7.16 (d, J=8.3 Hz, 2H), 6.86 (dd, J=9.0, 3.0 Hz, 1H), 6.79 (d, J=9.0 Hz, 1H), 4.51 (s, 2H), 3.37 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.71 (s, 6H), 1.61 (m, 4H), 1.40-1.25 (m, 8H), 0.94 (t, J=7.3 Hz, 3H), 0.90 (t, J=6.7 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:25]=[CH:24][C:22](/[N:23]=[CH:1]/[C:3]2[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(/C=N/c2ccc(Cl)cc2)cc1

Procedure:
tert-Butyl (4-formylphenoxy)acetate (17.4 g, 73.4 mmol) was dissolved in dry toluene (120 mL) and 4-chloroaniline (9.37 g, 73.4 mmol) was added. The mixture was refluxed in a Dean-Stark apparatus for 20 hours, cooled and concentrated under reduced pressure. Hexane was added and a precipitate formed. This precipitate was filtered, washed twice with cold hexane and dried. This afforded the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[C:25]([C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=1)#[CH:26].C1(C(O)(C#C)C)C=CC=CC=1>>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:26]#[C:25][C:27]4[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: C#Cc1ccc[n+]([O-])c1
Agent: C#CC(C)(O)c1ccccc1
Product: O=C(NC1CC1)c1cn(-c2cccc(C#Cc3ccc[n+]([O-])c3)c2)c2ncccc2c1=O

Procedure:
Following the procedure of EXAMPLE 15, but substituting N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 1 of EXAMPLE 6 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, and 3-ethynylpyridine N-oxide from Step 1 for 2-phenyl-3-butyn-2-ol, the N-cyclopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin4-one-3-carboxamide compound was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.O>CS(C)=O>[F:1][C:2]1[C:20]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A suspension of 5.0 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 6.2 g of 4-(4-fluorophenyl)-piperazine in 30 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature around 90° C. for approximately 4 hours. After cooling to approximately 20° C., 25 cm3 of water were added to the reaction mixture. The insoluble material was filtered off and washed with 2 times 25 cm3 of water. After recrystallizing once from 150 cm3 of dimethylformamide, 7.6 g of 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 318-9° C.
Reaction SMILES: [CH3:1]CCCCC.C[Si](C=[N+]=[N-])(C)C.[F:14][C:15]1[C:16]([C:21]([OH:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1>C(O)C.CN(C=O)C>[F:14][C:15]1[C:16]([C:21]([O:23][CH3:1])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCCCC
Reactant: O=C(O)c1ncccc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)c1ncccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A hexane solution (3 mL) of 2 M trimethylsilyldiazomethane was added to a benzene/methanol mixed solvent (1/1, 12 mL) of 3-fluoropyridine-2-carboxylic acid (250 mg), and stirred at room temperature for 30 minutes. The solvent was evaporated off under reduced pressure from the reaction solution, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=40/1) to obtain the entitled compound (238 mg).