Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.OC[C:12]1(N)[CH2:16][CH2:15][CH2:14][CH2:13]1.OCCN.C1(=O)CCCC1>>[CH2:3]1[C:2]2([CH2:7][O:9][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:1]2)[CH2:6][CH2:5][CH2:4]1
Reactant: NC1(C(=O)O)CCCC1
Reactant: NC1(CO)CCCC1
Solvent: NCCO
Solvent: O=C1CCCC1
Product: C1CCC2(C1)COC1(CCCC1)N2

Procedure:
1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B1c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. The hydroxyethylamine was reacted with cyclopentanone according to Method B4d, Step 1 to give 6-aza-12-oxadispiro[4.1.4.2]tridecane. The oxazolidine was reduced according to Method B4d, Step 2 to give 1-(cyclopentylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to 1-(cyclopentylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-l-1-azaspiro[4.4]nonane.
Reaction SMILES: C([O:4][C:5]1([CH2:21][N:22]([CH:26]([CH3:28])[CH3:27])C(=O)C)[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:8]=2[O:7][CH2:6]1)(=O)C.CO.[OH-].[Na+]>O>[OH:4][C:5]1([CH2:21][NH:22][CH:26]([CH3:28])[CH3:27])[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:8]=2[O:7][CH2:6]1
Reactant: CC(=O)OC1(CN(C(C)=O)C(C)C)COc2ccc(NS(C)(=O)=O)cc2OC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)NCC1(O)COc2ccc(NS(C)(=O)=O)cc2OC1

Procedure:
3-Acetoxy-3-(N-acetylisopropylaminomethyl)-7-methanesulfonamido-3,4-dihydro-2H-1,5-benzodioxepin (4.2 g., 10 millimole) in 20 ml. methanol is treated with 2 g. (50 millimoles) of sodium hydroxide in 20 ml. of methanol. The mixture is refluxed for 3 hours, cooled, and diluted with 400 mls. of water, neutralized with acid and extracted with ether. The combined ethereal solutions are washed with water, dried over anhydrous sodium sulfate, and evaporated to give 3-hydroxy-3-isopropylaminomethyl-7-methanesulfonamido-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][CH:14]=2)[N:7]=1.[Li+].[OH-]>C1COCC1.O>[Cl:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:18]=1)[CH:12]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[N:7]1
Reactant: COC(=O)CCc1cc(C)n(C(OCc2ccc(Cl)cc2)c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CCC(=O)O)nn1C(OCc1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ester 7 (0.31 g, 0.65 mmol) in THF (5 mL) was added a solution of LiOH (0.06 g, 1.40 mmol) in water (2 mL) and the resulting mixture was stirred at RT overnight. The volatiles were removed in vacuo. The residue was diluted with water (5 mL) and acidified to pH 1 with 2 M HCl. The acid 8 was isolated by filtration as a white solid and washed with water and dried overnight over KOH in a dessicator to yield 0.09 g (34%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].NC1C=CC(O)=C([N+]([O-])=O)C=1.C(Cl)(Cl)=O.[CH3:29][NH:30][CH3:31]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:30]([CH3:31])[CH3:29])=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CNC
Reactant: O=C=Nc1ccc(O)c([N+](=O)[O-])c1
Agent: Nc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Hydroxy-3-nitrophenylisocyanate (15.5 g), prepared as described by H. Ulrich et al., loc. cit., from 4-amino-2-nitrophenol and phosgene, is added to 100 g of a solution of 29% by weight of dimethylamine in toluene, and the mixture is stirred at room temperature for 2 hours. Evaporation under reduced pressure leaves a residue on recrystallization from water gives N-(4-hydroxy-3-nitrophenyl)-N',N'-dimethylurea, m.pt. 142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[C@@H]2C3[CH:46]=[CH:47][S:48]C=3CC[C@@H]2CCC)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:19]3[CH:46]=[CH:47][S:48][C:20]=3[CH2:22][CH2:21][C@@H:26]2[CH2:25][CH2:24][CH3:23])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCC[C@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(Br)nc1CC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCC[C@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-[Cis-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.50, 7.32, 7.08, 6.98, 5.73, 4.43, 2.98, 2.82, 2.62, 2.50, 2.10, 1.95, 1.76, 1.57–1.44, 1.42–1.18, 0.89; HRMS (FAB) calcd for C25H29Cl2N3S+H 474.1537, found 474.1544. Anal. Calcd for C25H29Cl2N3S: C, 63.28; H, 6.16; N, 8.86. Found: C, 63.61; H, 6.33; N, 8.65.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:21])C=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:9])=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(Br)cc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1ccc(Br)cc1
Reaction time: 4 h

Procedure:
4.06 g (20 mmol) of 4-bromothioanisole and 75 ml of dichloromethane were introduced into a round-bottomed flask and 6.3 g (20 mmol) of meta-chloroperbenzoic acid were added. Stirring was carried out at room temperature for four hours and the reaction mixture was poured into water. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and heptane (70/30). After evaporating the solvents, 1.22 g (28%) of the expected sulfoxide, with a melting point of 80°-81° C., was recovered.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][OH:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)([Cl:19])=[O:18]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:19][C:17]([O:16][CH2:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: O=C(Cl)Cl
Reactant: OCCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)OCCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h

Procedure:
To a solution of 2-(9-fluorenyl)ethanol 1.26 g, 6 mmol) in 10 ml of toluene and 4 ml of tetrahydrofuran (THF), was added dropwise with stirring phosgene (12.4 ml, 1.93M solution in toluene). The solution was stirred for 0.5 hours, then put under vacuum to remove the phosgene. Concentration yielded 2-(9-fluorenyl)ethyl chloroformate (6 mmol, 1.64 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][CH2:26][C:27](OC)=[O:28])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:17])[CH3:18])=[O:15])[C:11]([CH2:25][CH2:26][CH2:27][OH:28])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: COC(=O)CCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CCCO)c1ccccc1
Reaction time: 0.5 h

Procedure:
To 2.5 g (5.9 mmol) of ester 19-1 in THF at 0° C. was added 235 mg (6.2 mmol) of lithium aluminum hydride. After stirring for 30 min, the reaction was quenched with saturated NH4Cl, partitioned between EtOAc and 10% KHSO4, the organic phase was washed with water, saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 19-2 as a white solid. Data for 19-2: HRMS (ES) calc'd M+H for C22H24F2N2O2: 387.1879. Found: 387.1877.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:5]([C:8](=O)[CH:9](O)O)=[N:6][CH:7]=1.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=2[NH2:33])=[N:23][CH:24]=1.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:5]([C:8]2[N:32]=[C:28]3[N:29]=[CH:30][CH:31]=[C:26]([NH:25][C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:35])([F:34])[F:17])=[CH:24][N:23]=4)[C:27]3=[N:33][CH:9]=2)=[N:6][CH:7]=1
Reactant: Nc1nccc(Nc2ccc(C(F)(F)F)cn2)c1N
Reactant: O=C(c1ncc(Br)cc1C(F)(F)F)C(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1ccc(Nc2ccnc3nc(-c4ncc(Br)cc4C(F)(F)F)cnc23)nc1

Procedure:
Dissolve the crude 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)-2,2-dihydroxyethanone (800 mg, step 3) in 16.0 mL of EtOH, and then add N4-(5-(trifluoromethyl)pyridin-2-yl)pyridine-2,3,4-triamine (162 mg, step 5) followed by NaHCO3 (336 mg). Stir the reaction at room temperature for 18 hours under N2 atmosphere. Concentrate the reaction mixture under vacuum, and purify by column chromatography to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-D6) δ 9.405 (s, 1H), 9.287 (s, 1H), 9.127 (s, 1H), 9.109 (d, 1H, J=1.8 Hz), 8.905 (d, 1H, J=1.8 Hz), 8.728 (s, 1H), 8.380 (s, 1H), 7.883 (dd, 1H, J=0.7 Hz), 7.126(d, 1H, J=2.8 Hz). MS=516.85 (M+H). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)C>>[CH:10]([S:9][C:5]1[N:4]=[C:3]([CH2:2][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:28])=[O:15])=[CH:20][C:21]=2[O:26][CH3:27])[CH:8]=[CH:7][CH:6]=1)([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCc1ccc(O)c(OC)c1
Reactant: CC(C)Sc1cccc(CCl)n1
Product: COc1cc(CCC(=O)O)ccc1OCc1cccc(SC(C)C)n1
Yield: 55.3 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (32 mg, 0.15 mmol) obtained in Step C of Preparation Example 16 and 3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester (39 mg, 0.17 mmol) obtained in Step C of Preparation Example 38 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 61%).
Reaction SMILES: CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N:17]1([C:23]2[S:24][C:25]3[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=1>O.ClCCCl.C(O)(=O)C>[F:33][C:34]([F:44])([F:45])[O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:20]2[CH2:19][CH2:18][N:17]([C:23]3[S:24][C:25]4[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:26]=4[N:27]=3)[CH2:22][CH2:21]2)=[CH:38][CH:37]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: Oc1ccc2nc(N3CCNCC3)sc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: Oc1ccc2nc(N3CCN(Cc4ccc(OC(F)(F)F)cc4)CC3)sc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (1 ml) and a catalytic amount of acetic acid and sodium triacetoxyborohydride (0.14 g) were added to a 1,2-dichloroethane solution (5 ml) of 2-piperazin-1-yl-benzothiazol-6-ol (0.1 g) and 4-trifluoromethoxybenzaldehyde (0.067 ml) and stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure to afford the title compound as a colorless amorphous compound (80 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6]([OH:27])=[C:7]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:8](=[O:15])[C:9]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6]([OH:27])=[C:7]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:8](=[O:15])[C:9]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Cl)c(Cl)c2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(Cl)c(Cl)c21
Yield: 82.2 %

Procedure:
A solution of 1,1-dimethylethyl N-((7,8-dichloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.130 g, 0.314 mmol) in TFA (5.00 mL, 68.3 mmol) was stirred at 25° C. for 10 minutes. The resulting mixture was concentrated, azeotroped using DCM (2×100 mL), and dried in vacuo to give the title compound (0.0925 g). MS m/e=358 (M+H)+. Calculated for C15H13Cl2NO5 357.02.
Reaction SMILES: NC1N=CN=C2N(CC3OC(=O)C4C(C=3C3C=CC=CC=3)=CC=CC=4)N=C(I)C=12.[F:30][C:31]1[CH:32]=[C:33]([C:39]2[C:47]3[C:42](=[N:43][CH:44]=[N:45][C:46]=3[NH2:48])[NH:41][N:40]=2)[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1.Br[CH:50]([C:52]1[O:53][C:54](=[O:77])[C:55]2[C:60]([C:61]=1[C:62]#[C:63][CH2:64][N:65]([CH3:76])[C:66](=[O:75])[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH3:51]>>[NH2:48][C:46]1[N:45]=[CH:44][N:43]=[C:42]2[N:41]([CH:50]([C:52]3[O:53][C:54](=[O:77])[C:55]4[C:60]([C:61]=3[C:62]#[C:63][CH2:64][N:65]([CH3:76])[C:66](=[O:75])[O:67][CH2:68][C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)=[CH:59][CH:58]=[CH:57][CH:56]=4)[CH3:51])[N:40]=[C:39]([C:33]3[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=[C:31]([F:30])[CH:32]=3)[C:47]=12
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1C#CCN(C)C(=O)OCc1ccccc1
Agent: Nc1ncnc2c1c(I)nn2Cc1oc(=O)c2ccccc2c1-c1ccccc1
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3C#CCN(C)C(=O)OCc3ccccc3)c3ncnc(N)c23)c1
Yield: 34.2 %

Procedure:
The title compound was prepared following the procedure described for the synthesis of Intermediate D1, from 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 165 mg, 0.638 mmol) and benzyl (3-(3-(1-bromoethyl)-1-oxo-1H-isochromen-4-yl)prop-2-yn-1-yl)(methyl)carbamate (Intermediate C41, 290 mg, 0.638 mmol) to give Benzyl (3-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)prop-2-yn-1-yl)(methyl)carbamate (138 mg, 0.218 mmol, 34.2% yield) as yellow solid.
Reaction SMILES: [N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:5][CH2:4][CH:3]([C:6]([O:8]C(C)(C)C)=[O:7])[NH:2]1.C(O)(C(F)(F)F)=O.O>ClCCl>[C:17]1([CH2:16][O:15][C:13]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[NH:2]2)=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.2 %

Procedure:
To a solution of 3-(1,1-dimethylethyl) 1-(phenylmethyl) 1,3-pyrazolidinedicarboxylate (2.8 g, 9.14 mmol) in dichloromethane (DCM) (50 mL) was added TFA (42.2 mL, 548 mmol) and 10 mL of water. The reaction was stirred at 25° C. for 72 h. The solvent was removed under reduced pressure to give 1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (2.2 g, 8.79 mmol,) which was used directly without further purification. LC-MS (ES) m/e 250.8 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH:15]=[CH:14][N:13]=2)=[N:3]1.[ClH:28]>C(OCC)(=O)C>[ClH:28].[NH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Reaction time: 1 h
Yield: 12 %

Procedure:
tert-Butyl 2-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]ethylcarbamate (0.40 g, 1.0 mmol) was dissolved in ethyl acetate (20 ml), and 4 N hydrochloric acid in ethyl acetate (2 ml) was added thereto dropwise at 0° C. The mixture was stirred at the same temperature for 1 hr. The precipitates were collected by filtration and recrystallized from diisopropyl ether-methanol to give the titled compound (0.04 g, 12%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN(C)CCCl
Product: COc1ccccc1C1CCN(C(=O)c2cn(CCN(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-dimethyl-amine gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([C:4]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: c1ccc2c(c1)CCCN2
Agent: C[n+]1ccccc1Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-nicotinic acid (1.0 g, 6.35 mmol, 1.0 equiv; [CAS RN 2942-59-8]) in dichloromethane (40 mL) was added 1,2,3,4-tetrahydro-quinoline (0.93 g, 0.88 mL, 6.98 mmol, 1.1 equiv; [CAS RN 635-46-1]), triethylamine (1.28 g, 1.77 mL, 12.69 mmol, 2.0 equiv; [CAS RN 121-44-8]) and 2-chloro-1-methylpyridinium iodide (1.96 g, 6.98 mmol, 1.1 equiv; [CAS RN 14338-32-0]). The reaction mixture was stirred at rt for 2 h. To the residue was added a sat. solution of NaHCO3 (100 mL) and the solution extracted with dichloromethane (3×50 mL). The combined organic phases were dried over Na2SO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate affording 1.52 g (88%) of the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ2.07 (quint, J=6.6 Hz, 2H), 2.86 (t, J=6.6 Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 6.64 (br s, 1H), 6.93 (br t, J=4.0 Hz, 1H), 7.04 (br d, J=4.0 Hz, 1H), 7.08 (t, J=7.6 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.30 (s, 1H), 8.31 (d, J=7.6 Hz, 1H). MS (ISP): 273.1 [M+H]+.
Reaction SMILES: [Al].[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](O[Si](CC)(CC)CC)([C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:4]1>O>[F:14][C:13]([F:15])([F:16])[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=CC(=O)c2ccccc21
Agent: [Al]
Solvent: O
Product: Oc1ccc(C(F)(F)F)c2ccccc12
Temperature: 70 °C
Yield: 89.6 %

Procedure:
A strip of aluminum foil weighing 278 mg (10 mmol) was amalgamated by immersion in a solution of 2% mercuric chloride in water for 15 seconds, washed with absolute ethanol followed by diethyl ether, cut into small pieces, and added to a solution of 353 mg (1.0 mmol) of 1,4-dihydro-1-oxo-4-triethylsiloxy-4-trifluoromethylnaphthalene in 10 mL of 10% water - 90% tetrahydrofuran. The resulting mixture was heated at 70° C. for 1.5 hours, allowed to cool to room temperature, and filtered. The filter cake was washed with diethyl ether. Concentration of the combined filtrates gave a residue which was poured into 25 mL of water. The aqueous mixture was extracted with three 10 mL portions of dichloromethane. Combination, drying (MgSO4), and concentration of the organic layers gave a residue which was purified by PTLC (one 2 mm silica gel plate eluted with dichloromethane), affording 190 mg (90% yield) of 4-trifluoromethyl-1-naphthol as a white solid. An analytical sample was obtained by recrystallization from dichloromethane-hexane: mp 132°-133° C.; 1H NMR (CDCl3) δ5.50 (broad s, 1H), 6.79 (d, 1H, J=8 Hz), 7.50-7.80 (m, 3H), 8.10-8.45 (m, 2H); 19F NMR (CDCl3, relative to CFCl3) -59.5 ppm (s); IR (KBr) 3327, 1580, 1385, 1355, 1327, 1260, 1251, 1241, 1195, 1178, 1146, 1120, 1111, 1101, 1056, 767, cm-1 ; mass spectrum (70 eV) m/z (relative intensity) 212 (100, M+), 133 (32), 115 (100). Anal. Calcd. for C11H7F3O: C, 62.27; H, 3.33. Found: C, 61.82; H, 3.50.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:13][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([O:6][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CN(C)CCC(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Yield: 88.5 %

Procedure:
Following the procedure of Example 3, 17.9 g of 3-dimethylamino-1-phenyl-1-propanol and 14.1 g of 1-fluoro-4-nitrobenzene were reacted to provide 26.54 g of the subtitle intermediate as a red oil. Preparation of the oxalate salt of a small portion of the oil provided yellow crystals with a melting point of 155°-157° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10](Cl)[N:11]=[C:12]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:13]=2)[N:8]([CH3:25])[CH:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[K+]>C(O)(C)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][N:11]=[C:12]([CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:13]=2)[N:8]([CH3:25])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2c(Cl)nc(CN3CCOCC3)cc2c1=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)c1cn(C)c2cnc(CN3CCOCC3)cc2c1=O
Yield: 711.4 %

Procedure:
A mixture of ethyl-8-chloro-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-[1,7]naphthyridine-3-carboxylate (Preparation 45, 0.090 g), potassium acetate (0.015 g) and 10% Pd/C (20 mg) in isopropyl alcohol is hydrogenated (balloon) for 18 hours. The mixture is filtered through celite and the filter cake washed with MeOH. The solvent is evaporated and the crude solid chromatographed with CH2Cl2\CH3OH\TEA (90\9\1) to obtain 0.58 g (70%) of the title compound as an off-white solid. Physical characteristics: MS (ESI+) m/z 332 (M+H).