Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][NH:16][CH3:17].C1COCC1>>[CH3:15][N:16]([CH3:17])[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CNC
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Solvent: C1CCOC1
Product: CN(C)c1nc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A mixture of 2-chloro-6-(trifluoromethyl)nicotinic acid (APOLLO, 2.5 g, 11.1 mmol) and 2M N-methylmethanamine in THF solvent (50 ml, 25 mmol) was stirred for 24 hours at room temperature according to J. Med. Chem., 2005, 48, 71. Then the reaction mixture-was evaporated in vacuo to give the title compound (2.5 g, 96%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:33]>C1COCC1>[Br:33][CH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8]
Reactant: N#Cc1ccc(CO)cc1C#N
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)cc1C#N
Reaction time: 21 h

Procedure:
4-Hydroxymethyl-phthalonitrile from step 2 (1.3 g, 8.2 mmol) was dissolved in THF (41 ml) and treated with Ph3P (3.2 g, 12.3 mmol) followed by CBr4 (4 g, 12.3 mmol). The reaction mixture was stirred at room temp. for 21 hours. The solvent was removed in vacuo and the residue purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product. FAB MS: 222 m/z (M+ +H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][NH:16]3)=[N:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.Br[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][N:16]3[CH2:30][C:31]([OH:33])=[O:32])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2cccc3c2CCN3)nc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2cccc3c2CCN3CC(=O)O)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.3 %

Procedure:
6-(2,3-Dihydro-1H-indol-4-yloxy)nicotinic acid ethyl ester (1.13 g, 3.97 mmol) was dissolved in DMF (5 mL). To the solution were added triethylamine (0.665 mL, 4.77 mmol) and tert-butyl bromoacetate (0.704 g, 4.77 mmol), and the resulting solution was stirred for 16 hours at room temperature, followed by stirring for 4 hours at 50° C. Water (100 mL) was added and the resulting solution was extracted with ethyl acetate (100 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated to give a pale brown oil (1.58 g). This oil was dissolved in trifluoroacetic acid (10 mL) and the solution was stirred for 1 hour at room temperature. The solution was concentrated, and the pH of the solution was adjusted to 5 using saturated sodium bicarbonate solution. The resulting solution was extracted with a mixture of ethyl acetate (50 mL)-THF (25 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated. The obtained residue was recrystallized from a mixed solution of ethyl acetate and n-hexane to yield 0.220 g of the title compound as a pale brown powder.
Reaction SMILES: Br[CH:2]([CH:13]([CH3:15])[CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:4].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:13]([CH:2]1[C:3](=[O:4])[NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12]1)([CH3:15])[CH3:14]
Reactant: CC(C)C(Br)C(=O)Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C1Oc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-bromo-3-methylbutyryl)aminophenol (58.0 g), powdered potassium carbonate (38.3 g) and N,N-dimethylformamide (200 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water and the precipitate was collected to yield 2-isopropyl-2H-1,4-benzoxazin-3(4H)-one as crystals. Yield was 38.1 g (93.4%). Recrystallization from ethanol gave colorless plates, mp 118°-119° C. In the same manner as in Reference Example 1, the following compounds were obtained.
Reaction SMILES: F[C:2]1[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:20]1[CH:21]=[C:22]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34].BrC1C=C(NS(CC)(=O)=O)C=CC=1O[C:48]1[CH:53]=[CH:52]C(F)=CC=1F>>[CH:52]1([C:2]2[C:3](=[O:18])[N:4]([CH3:17])[CH:5]=[C:6]([C:20]3[CH:21]=[C:22]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:23]=[CH:24][C:25]=3[O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[F:34])[CH:7]=2)[CH2:53][CH2:48]1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(F)c1=O
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Product: Cn1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cc(C2CC2)c1=O

Procedure:
The title compound was prepared in a manner similar to Example 122, substituting 3-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one for 3-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one and N-[3-bromo-4-(2,4-difluorophenoxy)phenyl]methanesulfonamide for N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.46-0.54 (m, 2H) 0.77-0.88 (m, 2H) 1.93-2.07 (m, 1H) 2.98-3.05 (m, 3H) 3.44-3.51 (m, 3H) 6.89-6.95 (m, 1H) 7.00-7.12 (m, 3H) 7.13-7.19 (m, 1H) 7.21-7.25 (m, 1H) 7.39-7.48 (m, 1H) 7.71 (s, 1H) 9.56-9.82 (bs, 1H). LCMS (M+H)+=447.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].[F:13][C:14]([F:19])([F:18])[CH:15]([OH:17])[CH3:16]>>[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:17][CH:15]([CH3:16])[C:14]([F:19])([F:18])[F:13]
Reactant: CC(O)C(F)(F)F
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Product: CC(Oc1cc(C#N)ccc1N)C(F)(F)F

Procedure:
Is prepared in a similar manner as intermediate III.4 from 3-fluoro-4-nitro-benzonitrile and 1,1,1-trifluoro-propan-2-ol.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].Cl[C:9]1[CH:16]=[CH:15]C(C=O)=[CH:11][CH:10]=1.[C:17](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:6][CH2:7][CH2:17][CH2:5][CH2:4]1)[C:2]1[CH:15]=[CH:16][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCN(CC)CC
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1ccc(CN2CCCCC2)cc1
Reaction time: 16 h

Procedure:
Racemic 3-bromo-4,5-dihydroisoxazole III-43 was dissolved in trifluoroacetic acid (0.20 M with respect to isoxazole) and stirred at room temperature for 1 h. The solvent is then removed under vacuum and the crude residue is azeotroped with toluene (2×) to provide a the trifluoroacetic acid salt as a white solid which is then is dissolved in methylene chloride (0.06 M with respect to isoxozaole) after which triethylamine (2.5 equiv) and 4-chlorobenzaldehyde (1.25 equiv) are added followed by sodium triacetoxyborohydride (1.5 equiv). The reaction is allowed to stir for 16 h after which point is diluted with ethyl acetate and washed with dilute NaOH and then brine. The organic layer is then dried over sodium sulfate and concentrated under vacuum to provide crude material which was purified using flash silica gel chromatography (ethyl acetate/hexanes) to provide N-benzylpiperidine III-45 as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=316.6 m/z. Activity: C
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CN(C)[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O.CCOCC>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:21])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)N(C)C)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Yield: 56 %

Procedure:
2.6 g of indole and 8.6 g of N,N-dimethylanisamide were added to 2.6 ml of phosphorus oxychloride. The mixture was heated at 80°-85° C. for 3 hours. After cooling,50 ml of ether was added to the mixture. The reaction mixture was then poured into water and pH value was adjusted to 10 with aqueous solution of sodium hydroxide. The resulting precipitate was filtered out and then recrystallized from ethanol to obtain compound 1 in the form of white crystals. (Yield: 56%)
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.F[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28]C=O.C(O)(=O)C.[BH3-][C:36]#[N:37].[Na+]>CO>[O:15]=[C:6]1[C:5]2[C:4]3[CH2:3][CH:2]([NH:1][CH2:28][CH2:27][CH2:26][C:20]4[C:19]5[C:23](=[CH:24][CH:25]=[C:17]([C:36]#[N:37])[CH:18]=5)[NH:22][CH:21]=4)[CH2:14][O:13][C:12]=3[CH:11]=[CH:10][C:9]=2[CH2:8][NH:7]1
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Reactant: O=CCCCc1c[nH]c2ccc(F)cc12
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc2[nH]cc(CCCNC3COc4ccc5c(c4C3)C(=O)NC5)c2c1
Reaction time: 1.5 h
Yield: 69 %

Procedure:
To a mixture of (1) (60 mg, 0.294 mmol), 4-(5-fluoro-1H-indol-3-yl)butanal (21), 64 mg, 0.309 mmol) in acetic acid (37 μl, 0.62 mmol) and methanol (2 ml) was added NaBH3CN (37 mg, 0.59 mmol) in portions. Resulting mixture was stirred for 1.5 hr. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 and washed with 1 N NaOH and saturated NaCl. The organic solution was dried over Na2SO4 and concentrated in vacuo. The compound was purified on silica gel eluting with 60% EtOAc/Hexane to give (20) as a solid (78 mg, 69%). The title compound was dissolved in methylene chloride and treated with 1 equivalent of etherate HCl to give HCl salt. MS (ES) m/z 385.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[C:16]([C:20]1[CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26])([CH3:19])([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[C:16]([C:20]1[CH:28]=[C:24]([CH:23]=[C:22]([C:29]([N:11]2[CH2:10][CH2:9][CH:8]([O:7][C:6]3[CH:14]=[CH:15][C:3]([Cl:2])=[CH:4][CH:5]=3)[CH2:13][CH2:12]2)=[O:30])[CH:21]=1)[C:25]([OH:27])=[O:26])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(=O)O)c1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)cc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a stirred solution of 4-(4-chlorophenoxy)piperidine hydrochloride (100 mg, 0.40 mmol), 5-(tert-butyl)isophthalic acid (358 mg, 1.61 mmol), and N,N-diisopropylethylamine (0.28 mL, 1.61 mmol) in N,N-dimethylformamide (3 mL) was add HBTU (183 mg, 0.48 mmol) at room temperature. After stirring at 60° C. for 2 hours, the mixture was poured into water (5 mL). This was extracted with ethyl acetate (5 mL) and washed with water (5 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (eluting with dichloromethane/methanol=7:1) to give 121 mg (72% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH3:30])=[N:26][NH:27]2)=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)[N:4]=1.[C:31]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.O>[CH3:31][N:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)[N:4]=3)[CH:29]=2)[C:25]([CH3:30])=[N:26]1
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]c2cc(N(C)c3ccnc(Nc4cccc(CS(C)(=O)=O)c4)n3)ccc12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cc1nn(C)c2cc(N(C)c3ccnc(Nc4cccc(CS(C)(=O)=O)c4)n3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-N2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine (Example 23) (389 mg, 0.92 mmol) in DMF (4 ml) was added Cs2CO3 (600 mg, 1.84 mmol) followed by iodomethane (64 ul, 1.02 mmol). The mixture was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. Purification of crude product by prep TLC provided 260 mg of N4-(1,3-dimethyl-1H-indazol-6-yl)-N4-methyl N2-{3-[(methylsulfonyl)methyl]-phenyl}-2,4-pyrimidinediamine. 1H NMR (300 MHz, d6DMSO) δ 9.25 (s, 1H), 7.86 (d, J=6.0 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.58 (s, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 5.83 (d, J=6.0 Hz, 1H), 4.28 (s, 2H), 3.92 (s, 3H), 3.49(s, 3H), 2.87 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 437 (M+H).
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:16][CH3:17])[C:8]=2[N+:13]([O-])=O)[N:3]=1>[Pd].C(O)(=O)C.CO.C(Cl)Cl.[OH-].[Na+]>[NH2:13][C:8]1[C:7]([O:16][CH3:17])=[C:6]([O:18][CH3:19])[CH:5]=[C:4]2[C:9]=1[C:10]([OH:12])=[N:11][C:2]([OH:1])=[N:3]2
Reactant: COc1cc2nc(O)nc(O)c2c([N+](=O)[O-])c1OC
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2nc(O)nc(O)c2c(N)c1OC
Yield: 73.6 %

Procedure:
A mixture of the product of step (b) (35.0 g, 0.13 mol) and 10% palladium on carbon (4.0 g) was suspended in glacial acetic acid (200 ml) and hydrogenated at 50 psi (3.4 atm) and 5° C. for 2.5 days. The reaction was then cooled, suspended in MeOH/CH2Cl2 (1/1 v/v, 1 L) and filtered. The residue was transferred to a soxhlet apparatus and continually extracted with MeOH for 3 days. Evaporation afforded a grey solid which was dissolved in 2N NaOH, filtered through a pad of silica, washing with H2O. The filtrate was then acidified with concentrated HCl. The resulting precipitate was isolated by filtration, washing sequentially with H2O and acetone, then dried in vacuo at 60° C. to give the subtitle compound as a white solid (22.7 g, 73%). Rf 0.42 (EtOAc/MeOH 95/5, v/v). MS m/z 238 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)=[CH:27][NH:26][N:25]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[N:25]3[N:26]=[CH:27][C:28]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)=[C:24]3[N:23]=2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2]
Reactant: CCOc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: CCOc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccnc(C)c4)c3n2)cc1C(F)(F)F
Yield: 62.2 %

Procedure:
Reaction of 1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (164 mg, 0.5 mmol), prepared from 4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (145 mg, 62%). MS (ISP) 467.2 [(M+H)+]; mp 250° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=[CH2:4].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K]>CN(C)C=O>[C:7]1(=[O:17])[N:11]([CH2:5][C:3](=[CH2:4])[CH2:2][Cl:1])[C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12
Reactant: C=C(CCl)CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: C=C(CCl)CN1C(=O)c2ccccc2C1=O
Temperature: 50 °C

Procedure:
A mixture of 3-chloro-2-chloromethyl-1-propene (6.55 g, 50 mmol) and potassium phthalimide (5.6 g, 30 mmol) in anhydrous dimethylformamide (200 ml) was heated two days at 50° C. Then the mixture was concentrated in vacuo and, after usual work-up, the product was purified by flash chromatography on silica gel (ethyl acetate:hexane; 15:85) (4.2 g, 78%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.N1C=CC=CC=1>C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:24][CH2:23][CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CNC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC3)c(F)cc2c1=O
Yield: 89.2 %

Procedure:
A mixture of 0.6 g (2.1 mmoles) of 1-cyclopropyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid with 0.25 g (4.4 mmoles) of azetidine, 8 ml of pyridine and 1 ml of triethylamine is maintained at 110°-120° C. for 2 hours in a closed vessel. After cooling, evaporating under vacuum, filtering and washing, 0.6 g (88%) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 289°-93° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-:12])([OH:11])=[O:10]>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:9]([O-:12])=[O:10])=[C:4]([OH:8])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(Br)c1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(Br)cc1O
Product: O=[N+]([O-])c1ccc(O)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromophenol (10 g) in chloroform (50 ml) and acetic acid (50 ml) was added 70% nitric acid (60 ml) dropwise on an ice bath, and the solution was stirred for 1 hour. The reaction mixture was poured into ice water, extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (4.1 g) and 5-bromo-2-nitrophenol (1.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([CH:14]3[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.[C-:38]#[C-:39].[Si]([Li])(C)(C)C>C1COCC1>[C:21]([O:20][C:18]([N:16]1[CH2:17][CH:14]([C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=2)=[C:2]3[Cl:1])([OH:13])[C:38]#[CH:39])[CH2:15]1)=[O:19])([CH3:22])([CH3:24])[CH3:23]
Reactant: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: [C-]#[C-]
Agent: [Li][Si](C)(C)C
Solvent: C1CCOC1
Product: C#CC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a flask containing tert-butyl 3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)azetidine-1-carboxylate (500 mg, 0.93 mmol, Intermediate 13: step b) was added THF (10 mL) and the solution was cooled to 0° C. Then, TMS-lithiumacetylide (0.5 M in Et2O, 2.0 mL, 1 mmol) was added and the reaction was allowed to warm gradually to room temperature. After 5 hours, additional TMS-lithiumacetylide (2 mL, 1.0 mmol, 0.5 M in Et2O) was added and the reaction mixture was stirred at room temperature overnight. After 24 hours, the mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (1% acetone-DCM increasing to 5% acetone) provided a mixture of title compound and the silylated title compound. To a flask containing tert-butyl-3-(1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-hydroxy-3-(trimethylsilyl)prop-2-yn-1-yl)azetidine-1-carboxylate (220 mg, 0.35 mmol) was added MeOH (8 mL) followed by 2 M aqueous KOH (0.4 mL) at room temperature. After stirring for 15 minutes, the reaction was concentrated and chromatographed directly on silica gel (5% acetone-DCM increasing to 25% acetone) to provide the title compound as an amorphous white solid. 1H NMR (500 MHz, CDCl3) δ 8.36 (d, J=1.1 Hz, 1H), 7.88-7.79 (m, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 4.35 (s, 2H), 4.19-4.12 (m, 1H), 4.07 (s, 3H), 4.01-3.94 (m, 1H), 3.91-3.79 (m, 2H), 3.14-3.03 (m, 1H), 2.81 (s, 1H), 2.68 (s, 1H), 1.43 (s, 9H); MS (ESI): mass calcd. for C29H28ClF3N2O4, 560.2, m/z found 504.9 [M-t-Butyl]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: C=Cc1ccccc1
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3ccccc3n2CCc2ccccc2)C1
Yield: 9.9 %

Procedure:
The title compound was prepared according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-5-phenethyl-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example 5) (100 mg, 0.5 mmol), styrene (1 mL, 8.64 mmol) and NaH (200 mg, 5 mmol) in DMF (4 ml) at 150° C. for 16 h to obtain 15 mg of 2-ethyl-2,3,4,5-tetrahydro-5-phenethyl-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:21]=[CH:20][C:13]3[N:14]([CH:17]([CH3:19])[CH3:18])[N:15]=[N:16][C:12]=3[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[CH:21]=[CH:20][C:13]3[N:14]([CH:17]([CH3:18])[CH3:19])[N:15]=[N:16][C:12]=3[CH:11]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: CC(C)n1nnc2cc(C(=O)c3ccc(F)cc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)n1nnc2cc(C(O)c3ccc(F)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a stirred solution of 17 parts of (4fluorophenyl) [1-(1-methylethyl)-1H-benzotriazol-5-yl]methanone in 80 parts of ethanol were added 3.4 parts of sodium tetrahydroborate. After stirring for 1 hour at room temperature, the reaction mixture was neutralized to pH 7. The reaction mixture was concentrated and the product was extracted with ethyl acetate. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 10.7 parts (62.5%) of α-(4-fluorophenyl)-1-(1-methylethyl)-1H-benzotriazole-5-methanol as a residue (int. 4).