Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[C:6]([CH3:12])=[N:7][C:8](F)=[CH:9][CH:10]=1.O>CS(C)=O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:1]#[N:2])=[N:7][C:6]=1[CH3:12]
Reactant: [C-]#N
Reactant: Cc1nc(F)ccc1Br
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(C#N)ccc1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
NaCN (4 g, 82 mmol) was added to a solution of 3-bromo-6-fluoro-2-methyl-pyridine (4 g, 21 mmol) in DMSO (100 mL) The mixture was stirred for 2 h at 100° C., poured into H2O (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, 10 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.6 g, 15%) as white solid; MS (EI): m/e=197.0 [1\4+H]+.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][C:9]=2[CH3:17])=[CH:4][CH:3]=1.[OH-].[NH4+:19]>O1CCOCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([S:13]([NH2:19])(=[O:15])=[O:14])=[CH:10][C:9]=2[CH3:17])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(S(=O)(=O)Cl)sc1-c1ccc(F)nc1
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(S(N)(=O)=O)sc1-c1ccc(F)nc1
Reaction time: 2 h

Procedure:
5-(6-Fluoro-pyridin-3-yl)-4-methyl-thiophene-2-sulfonyl chloride (310 mg, 1.06 mmol) was dissolved in dioxane and cooled with an ice-bath. Under stirring was added dropwise an excess of ammonium hydroxide solution 25%. After two hours at room temp the reaction was neutralized and the dioxane was evaporated. The reaction mixture was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over magnesiumsulfat-dihydrate, filtered and evaporated. The crude product was purified on silica-gel with eluent ethyl acetate/n-heptane to give 218 mg of the title compound as a white solid. MS (ES): m/e 271.2 (M−H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:19](=[N:21]O)C)[CH:17]=[CH:18][C:13]=2[N:12](C)[C:11](=[O:24])[CH:10]([CH3:25])[N:9]=1.[C:26](C1C=CC2NC(=O)C(C)(C)N=C(C3C=CC=CC=3F)C=2C=1)(=O)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:19]#[N:21])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:24])[C:10]([CH3:26])([CH3:25])[N:9]=1
Reactant: CC(=NO)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2C
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2
Product: CC1(C)N=C(c2ccccc2F)c2cc(C#N)ccc2NC1=O

Procedure:
From 33.74 g (0.169 mol) of 5-(o-fluorophenyl)-2,3-dihydro-3,3-dimethyl-2-oxo-1H-1,4-benzodiazepine-7-carbonitrile there is obtained in analogy to paragraph (h) of Example 1 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 206°.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:13][CH2:12]2)=[N:3]1.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:27](=[O:30])[CH:28]=[CH2:29])=[C:21]([CH3:26])[CH:20]=3)[CH2:15][CH2:16]2)=[N:3]1
Reactant: C=CC(=O)Cl
Reactant: Cc1cc(CCN2CCN(c3nsc4ccccc34)CC2)ccc1N
Agent: Cl
Product: C=CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C
Yield: 74 %

Procedure:
Starting with 4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenylamine hydrochloride (0.60 g, 1.702 mmol) and acryloyl chloride (0.138 mL, 1.702 mmol) and following the procedure outlined in Example 512, N-{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-acrylamide (0.512 g, 1.259 mmol) was obtained. Yield=74%. 100% purity at 254 nM; LCMS (APCI): 407.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (bs, 1H), 9.50 (s, 1H), 8.11 (d, J=8.22 Hz, 1H), 8.07 (d, J=8.22 Hz, 1H), 7.55 (t, J=7.3 Hz, 1H), 7.45–7.37 (m, 2H), 7.11 (s, 1H), 7.05 (d, 7.63 Hz, 1H), 6.50 (dd, J=10.09, J=17.08, 1H), 6.18 (dd, J=2.13 Hz, J=17.08 Hz, 1H), 5.69 (dd, J=2.05 Hz, J=10.05 hz, 1H), 4.10–4.00 (m, 2H), 3.70–3.59 (m, 2H), 3.50–3.33 (m, 4H), 3.29–3.21 (m, 1H), 3.07–2.95 (m, 2H), 2.16 (s, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]2[CH:18]=[N:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:8]2[CH2:7]1>FC(F)(F)C(O)=O>[O:13]=[C:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]2[CH:18]=[N:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:8]2[CH2:7][NH:6]1
Reactant: CCOC(=O)c1ncn2c1CN(Cc1ccc(OC)cc1OC)C(=O)c1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncn2c1CNC(=O)c1ccccc1-2

Procedure:
90 g (214 mmol) of ethyl 5,6-dihydro-5-(2,4-dimethoxybenzyl)-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate are heated to reflux while stirring for 3 hours in 300 ml of trifluoroacetic acid. After evaporation in vacuo, the residue is treated with water and made alkaline with 10 percent potassium carbonate solution. The separated material is filtered off under suction, washed with water and dried in vacuo. After recrystallisation from chloroform/hexane, there is obtained ethyl 5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 248°-250° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=1.Cl.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[O:30]=[C:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][S:12]([C:10]3[S:11][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:8][CH:9]=3)(=[O:14])=[O:13])=[CH:19][CH:20]=2)[CH2:25][CH2:26]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(-c4ccccn4)s3)cc2)CC1

Procedure:
The title compound was prepared from 5-pyridin-2-yl-thiophene-2-sulphonyl chloride and 1-(4-amino-phenyl)-piperidine-4-one (which was obtained in Example 224) according to the procedure B of Example 225 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.37 (t, J=6.0 Hz, 4H), 3.52 (t, J=6.0 Hz, 4H), 6.89 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0 Hz, 2H), 7.39 (dd, J=4.2, 1.5 Hz, 1H), 7.42 (d, J=2.1 Hz, 1H), 7.76 (d, J=2.1 Hz, 1H), 7.90 (dd, J=7.8, 1.5 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 8.53 (d, J=4.2 Hz, 1H), 10.05 (s, 1H); MS (ES) m/z: 413.9 (MH+); HRMS Calcd. for C20H19N3O3S2 (M+): 413.0867. Found: 413.0877.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11](Cl)=[O:12])[O:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[CH3:21][NH:22][CH3:23].O>C(OCC)(=O)C>[CH3:21][N:22]([CH3:23])[C:11]([CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[O:4][CH2:3][CH2:2][O:1]2)=[O:12]
Reactant: O=C(Cl)C1CCCCC12OCCO2
Reactant: CNC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(=O)C1CCCCC12OCCO2
Temperature: 20 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a 1 M solution of 1,4-dioxa-spiro[4.5]decane-6-carbonyl chloride in toluene (1 mL, 1 mmol) was added at 0° C. a 7.9 M solution of dimethylamine in water (1.27 mL, 10 mmol). The mixture was stirred at 20° C. for 1 h, then diluted with ethyl acetate (40 mL), and washed successively with water (10 mL), saturated aqueous sodium carbonate solution (10 mL), 1 N hydrochloric acid, and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the title compound (69 mg, 32%) as colorless oil. MS ISP (m/e): 214.3 (100) [(M+H)+].
Reaction SMILES: C(OC(=O)/[CH:5]=[C:6]1/[C:7]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:8]=2[O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]/1=2)C.[OH-].[Na+].C([O-])(=O)C.[Li+].[Br:31]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CO.C(#N)C.O>[Br:31]/[CH:5]=[C:6]1/[C:7]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:8]=2[O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]/1=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C1/c2ccc(F)cc2OCc2c(F)cccc21
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CC#N
Solvent: CO
Product: Fc1ccc2c(c1)OCc1c(F)cccc1/C2=C\Br
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
Heat a stirred slurry of (E)-(3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidene)-acetic acid ethyl ester (601 mmol, 190 g) in methanol (1.9 L) and 5 N sodium hydroxide (1.20 mol, 240 mL) to 50° C. for 2 h. Remove the methanol in vacuo and reslurry the resulting black sludge in water (3 L). Add 5 N hydrochloride acid (250 mL) over 45 min, stir for 2.5 h, filter, and rinse the residue with water (4×200 mL). Dry the gray solid in vacuo at 60° C. overnight, and 80° C. for 6 h. Dissolve the solid (still wet, contains approximately 95 g of water) and lithium acetate (60.1 mmol, 4 g, 0.1 eq) in acetonitrile (1.7 L) and stir for 15 min. Add N-bromosuccinimide (661 mmol, 118 g) in one portion and stir for 2.5 h. Add 0.25 M sodium thiosulfate (400 mL), followed by saturated aqueous sodium bicarbonate (400 mL), and water (900 mL). Stir the mixture for one hour at room temperature and then stir for 2 h on an ice bath. Filter the mixture and rinse with cold acetonitrile (300 mL). Dry overnight in vacuo at 50° C. to obtain the title compound as a light beige solid (173.3 g, 89%). 1H NMR (DMSO-d6) δ 5.25 (s, 2H), 6.67 (dd, 1H), 6.81 (dt, 1H), 7.20 (s, 1H), 7.22 (d, 1H), 7.28 (t, 1H), 7.36 (dd, 1H), 7.48 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=[O:9])=[CH:6][CH:7]=1
Reactant: Brc1ccc(C2(c3ccccc3)CO2)cc1
Solvent: c1ccccc1
Product: O=CC(c1ccccc1)c1ccc(Br)cc1
Reaction time: 0.05 h

Procedure:
A solution of 2-(4-bromophenyl)-2-phenyloxirane 51 (5.27 g, 19.15 mmol) and BF3OEt2 (3.29 g, 23.20 mmol) in benzene (50 mL) was shaken vigorously in a separatory funnel for 2 minutes then allowed to stand for 3 minutes. The resulting solution was washed twice with aq. sat. NaHCO3 and the organic layer was separated, dried over Na2SO4 and concentrated to afford 2-(4-bromophenyl)-2-phenylacetaldehyde 52. The crude was used in the next step.
Reaction SMILES: C(#N)C.[I-:4].[Na+].Br[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[O:8]1.CC(OCC1CS[C@@H]2[C@H](NC(CC3SC=CC=3)=O)C(=O)N2C=1C(O)=O)=O>CS(C)=O>[I:4][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[O:8]1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: [I-]
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C1OC(I)c2ccccc21
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
Iodophthalide was prepared immediately prior to use by mixing acetonitrile solutions of sodium iodide (1.5mmole) and bromophthalide (1.5mmole) and stirring for 3 minutes. This solution was filtered (to remove precipitated sodium bromide) into an ice cooled DMSO solution of cephalothin (1mmole), stirred 10 minutes and poured into ice water to precipitate the required ester. Yield of crude, neutral product after work up -- 90%. TLC and NMR indicate >90% ceph-3-em ester. δ (CDCl3 /trace DMSO) = 2.08 (d, 3H, --OCOCH3), 3.61 (broad s, 2H, C2--H), 3.88 (s, 2H, α-CH2), 4.6 - 5.4 (ABq + d, 3H, --CH2O-- + C6), 5.6 - 6.0 (m, 1H, C7) 6.9 - 7.4 (d, + t, 3H, thienyl aromatics), 7.5 - 8.2 (m, ca. 5H, phthalidyl aromatics and --OCHO--), 8.2 - 8.6 (2d, 1H, amide N-H). νmax (CHCl3) 3370, 2960, 1793, 1743, 1682, 1505, 1230, 982cm-1 ; λmax (EtOH) 275nm (ε, 7000)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:29][C:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)([OH:27])[CH3:28])[C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC1(c2ccc(F)cc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(C)(O)c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.5 %

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (61 mg, 0.254 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.852 mmol) was added and stirred at RT for 5 min. 2-(4-Fluorophenyl)-2-methyloxirane (194 mg, 1.27 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 150 mg of (1-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol) as the TFA salt. 1H NMR (DMSO-d6, TFA salt) δ (ppm): 7.40 (s, 1H), 7.30-7.18 (m, 3H), 7.0-6.80 (m, 3H), 4.40-4.25 (d, 2H), 4.25-4.15 (d, 2H), 3.40-3.20 (d, 2H), 3.20-3.00 (m, 4H), 2.90 (s, 3H), 1.50 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:30]=[C:29](F)[CH:28]=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:29]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([F:19])[CH:30]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 110 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenol (1.05 g, 5.34 mmol) in DMSO (10 mL) was added potassium carbonate (2.20 g 13.4 mmol, 2.5 eq.) and the suspension was left to stir for 5 minutes after which, ethyl 2,4-difluorobenzoate (1.0 g, 5.34 mmol) was added and the reaction mixture left to stir at 110° C. under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and quenched with 1N NaOH (10 mL) then extracted into ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered and evaporated. The resulting residue was purified by column chromatography (SiO2, 1:1 ethyl acetate: heptane) to give the desired product (mixture of regioisomers) as a colourless oil (1.8 g, 93% yield). This was taken directly on to the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[OH:16])=[CH:5][CH:4]=[N:3]1.Br.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1O
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCc1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 110.7 %

Procedure:
A mixture of 2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol (100 mg, 0.46 mmol), 2-bromomethylpyridine hydrobromide salt (140 mg, 0.55 mmol) and potassium carbonate (158 mg, 1.15 mmol) in DMSO (4 mL) was stirred at 100° C. overnight. The crude was purified by HPLC to provide the title compound as a brown solid (158 mg, 81%). Exact mass calculated for C16H14N4O3 310.1, found 311.2 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH2:4]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:1][CH2:2][CH:3]3[CH2:8][CH2:7][CH2:6][N:5]([C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[C:11]([O:13][CH3:14])=[O:12])[CH2:4]3)=[O:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC(=O)c1ccccc1N1CCCC(CN)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1N1CCCC(CNC(=O)c2ccc(-c3ccc(Cl)cc3)cc2)C1
Temperature: 0 °C
Yield: 76.1 %

Procedure:
Methyl 2-[3-(aminomethyl)piperidin-1-yl]benzoate (78.2 mg, 0.315 mmol) was dissolved in N,N-dimethylformamide (3 mL) and the solution was chilled to 0° C. While this solution was stirred, 4′-chlorobiphenyl-4-carboxylic acid (81.1 mg, 0.349 mmol), 1-hydroxybenzotriazole monohydrate (54.1 mg, 0.353 mmol), N-methylmorpholine (90 μL, 0.819 mmol) and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (64.6 mg, 0.337 mmol) were added and the mixture was stirred for 20 min. The reaction mixture was then stirred at room temperature for 12 hours. Subsequently, the mixture was extracted with ethyl acetate and the organic layer washed sequentially with 5% aqueous citric acid, a saturated aqueous sodium bicarbonate solution, water and brine. The washed product was dried over anhydrous sodium sulfate and the solvent was concentrated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=2:1) gave 111 mg (76%) of the desired compound as a colorless powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14].[CH2:24]=[O:25]>CC(OC)(C)C>[CH3:19][O:18][C:16](=[O:17])[C:15]([CH2:13][CH3:14])([CH2:24][OH:25])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C=O
Reactant: CCCCC(CC)C(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: COC(C)(C)C
Product: CCCCC(CC)(CO)C(=O)OC
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
9.8 ml (0.070 mol) of diisopropylamine are added dropwise at 20° C. to a solution of 24.4 ml (0.065 mol) of n-butyllithium (2.7 M in heptane) in 25 ml of MTBE, and the mixture is stirred at −20° C. for 30 min. Within approx. 10 min, 10 g (0.063 mol) of methyl 2-ethylhexanoate are added dropwise at −20° C., and the mixture is stirred at 20° C. for a further 30 min and subsequently admixed with 5.7 g (0.19 mol) of paraformaldehyde. After 30 min at −20° C., the mixture is stirred at 0° C. for 2 h. After the removal of the solvent at 20° C. and 20 mbar, 20 ml of MTBE and 40 ml of saturated aqueous solution of ammonium chloride are added to the oily residue (approx. 20 g) and the mixture is stirred at RT for 2 h. The organic phase is removed, the aqueous phase is re-extracted 1× with 20 ml of MTBE and the combined organic phases are concentrated on a rotary evaporator. The yield of pure product is 86% (GC).
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:21][CH:20]([O:22][CH3:23])[CH2:19]2)=[C:14]([F:24])[CH:13]=1)(OCC1C=CC=CC=1)=O.C([Li])CCC.[C:30]([O:35][CH2:36][C@@H:37]1[O:39]C1)(=[O:34])CCC>O1CCCC1>[F:24][C:14]1[CH:13]=[C:12]([N:11]2[CH2:1][C@H:36]([CH2:37][OH:39])[O:35][C:30]2=[O:34])[CH:17]=[CH:16][C:15]=1[N:18]1[CH2:21][CH:20]([O:22][CH3:23])[CH2:19]1
Reactant: COC1CN(c2ccc(NC(=O)OCc3ccccc3)cc2F)C1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1CN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
A solution of N-(carbobenzyloxy)-3-fluoro-4-(3-methoxy-1-azetidinyl)aniline (0.865 g, 2.62 mmol) in dry tetrahydrofuran (10 mL) was cooled to -78° C. under a nitrogen atmosphere and treated with n-butyllithium (1.65 mL of a 1.6M solution in hexanes, 2.65 mmol). After stirring at -78°0 C. for 15 min, the reaction mixture was treated with (R)-glycidyl butyrate (0.374 mL, 2.65 mmol). The cooling bath was then removed and the reaction mixture allowed to warm to ambient temperature. After 1 h the reaction was judged complete by TLC analysis. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (0.5 mL) and concentrated under reduced pressure to a yellow solid. Chromatography over silica gel (10 g), eluting with a gradient of 1-2% methanol/chloroform afforded, after concentration of appropriate fractions, 0.530 g (68%) of the title compound as an off-white solid with mp 131°-132° C. and MS(EI) 296 (M+).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH:12]([O:31][C:32](=[O:34])[CH3:33])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]2[CH2:28][O:27]C(C)(C)[O:25]2)=[CH:15][CH:14]=1)(=[O:10])[CH3:9]>CO.C(OCC)(=O)C>[C:32]([O:31][CH:12]([O:11][C:8](=[O:10])[CH3:9])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[CH2:28][OH:27])=[CH:17][CH:18]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(OC(C)=O)c1ccc(OCCCCC2COC(C)(C)O2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC(OC(C)=O)c1ccc(OCCCCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Trifluoroacetic acid (1.5 ml) was added to a solution of 7 (5.8 g, 15.26 mmol) in 20% aqueous methanol. The solution was stirred for 40 min at room temperature and then diluted with 400 ml of ethyl acetate and washed with 400 ml of 5% sodium bicarbonate solution followed by 400 ml of water. The organic solution was dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography eluting with a gradient of 50% hexane in ethyl acetate to 100% ethyl acetate to 5% methanol in ethyl acetate. The pure product fractions were evaporated affording an oil: 1.1 g (20%) yield; TLC (5% methanol in ethyl acetate), Rf=0.64; 1H NMR (CDCl3) 7.62 (1H, s, acetal CH), 7.44 (2H, d, J=8.7 Hz, aromatic), 6.90 (2H, d, J=8.6 Hz, aromatic), 3.98 (2H, t, J=6.3 Hz, CH2), 3.68 (1H, m, CH), 3.46 (2H, m, CH2), 2.11 (6H, s, Acetyl), 1.82 (2H, m, CH2), 1.55 (4H, m, CH2). Anal. Calcd for C17H24O7: C, 59.99; H, 7.11. Found: C, 60.26; H, 7.08.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:11]=[C:12]([CH3:18])[C:13]([O:15]CC)=[O:14].[OH-].[Na+].Cl>O1CCCC1>[NH2:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:11]=[C:12]([CH3:18])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C)=Cc1ccc(N(C)C)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=Cc1ccc(N(C)C)cc1N)C(=O)O

Procedure:
ethyl 3-(2-amino-4-dimethylaminophenyl)-2-methyl-2-propenate was dissolved in tetrahydrofuran (THF); and, with 10 ml of a 1-N aqueous sodium hydroxide solution being added thereto, the mixture was reacted for 4 hours at 40° C. After the completion of the reaction was verified by TLC, the mixture was cooled with 1-N hydrochloric acid being added thereto, and the precipitated crystal was filtered out, whereby the aimed compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.[H-].[Na+].[CH:26]12[O:32][CH:31]1[CH2:30][CH2:29][CH2:28][CH2:27]2>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)=[N:10][N:11]([CH:30]3[CH2:29][CH2:28][CH2:27][CH2:26][CH:31]3[OH:32])[C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: COc1nccc2[nH]nc(-c3ccc(N4CCOCC4)cc3)c12
Reactant: C1CCC2OC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2C1CCCCC1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of 4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (500 mg) obtained in Step G of Example 305 in anhydrous DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 72.0 mg), and the mixture was stirred for 30 min. To the reaction mixture was added 7-oxabicyclo[4.1.0]heptane (1.60 g) at room temperature, and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was added to ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (400 mg).