Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9]C)=[O:8])[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCOc1cc(C(=O)OC)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cc(C(=O)O)ccc1OC
Yield: 91.1 %

Procedure:
A mixture of methyl 3-ethoxy-4-methoxybenzoate (4.42 g), methanol (160 mL) and IN-sodium hydroxide solution (40 mL) was heated for 2 hours under reflux. The reaction mixture was acidified with 1N-hydrochloric acid to pH 4, and the organic solvent was removed by evaporation. The aqueous layer was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with hexane to give 3-ethoxy-4-methoxybenzoic acid as colorless powders (3.76 g). NMR (CDCl3, δ): 1.50 (3H, t, J=7 Hz), 3.95 (3H, s), 4.17 (2H, q, J=7 Hz), 6.92 (1H, d, J=8 Hz), 7.60 (1H, d, J=4 Hz), 7.76 (1H, dd, J=4, 8 Hz); Mass m/z: 195(M+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][CH2:4][CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].N12CCCN=C1CCCCC2.[N+:25]([CH3:28])([O-:27])=[O:26]>>[F:1][C:2]([F:12])([F:13])[CH2:3][CH2:4][CH:5]([CH2:28][N+:25]([O-:27])=[O:26])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C=CCCC(F)(F)F
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC(CCC(F)(F)F)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To ethyl 6,6,6-trifluorohex-2-enoate a6 (54.42 g, 0.277 mol, 1 eq) in nitromethane (250 ml) is added in one portion 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 41.5 ml, 0.277 mol, 1 eq). The reaction mixture is stirred at room temperature for 3 hours, then the nitromethane layer is washed two times a 2N HCl aqueous solution (250 ml). The cumulated aqueous layers are extracted by ethyl acetate (2×250 ml). The cumulated organic layers are dried over MgSO4, filtered and condensed under vacuum to yield 50 g of crude ethyl 6,6,6-trifluoro-3-(nitromethyl)hexanoate a7 which is used in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].CN(C)C=O.Br[CH2:34][F:35]>O.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:16][O:17][CH2:34][F:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc(C)cc2)cc1OC
Reactant: FCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)C(=COCF)c2ccc(C)cc2)cc1OC
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Two hundred milligrams (200 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-methylphenyl)acrylamide (0.586 mmol), 28 mg (0.70 mmol) of 60% sodium hydride, 2 ml of anhydrous N,N-dimethylformamide and 1 ml of anhydrous diethyl ether were mixed and 0.5 ml of bromofluoromethane was added thereto at −5° C. The mixture was stirred at −5° C. for 30 minutes and then stirred at 0° C. for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel preparative thin layer chromatography (eluent, hexane:ethyl acetate=2:1) to give 205 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-fluoromethoxy-2-(4-methylphenyl)acrylamide (the present compound 1-4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: OCc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(Br)ccc1OCc1cccnc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 137.9 %

Procedure:
To a suspension of 4-bromo-2-(trifluoromethyl)phenol (8.00 g) in 1,4-dioxane (100 ml), triphenylphosphine (10.99 g) and 3-pyridylcarbinol (3.88 g) were added. Then diisopropyl azodicarboxylate (8.93 g) was dropwised and stirred at 20° C. for 18 h. The mixture was evaporated off the solvent, diethyl ether (100 ml) and iso-hexane (25 ml) were added and stirred at 20° C. for 2 h, stood for 3 days, filtered and washed with diethyl ether and iso-hexane. The filtrate was concentrated and purified by Biotage SNAP cartridge KP-Sil column (100 g, heptane:ethyl acetate=1:0, 2:1 to 1:1) to give 15.2 g light yellow solid as 3-((4-bromo-2-(trifluoromethyl)phenoxy)-methyl)pyridine (70% purity).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([P:12](=[O:19])([O:16]CC)[O:13]CC)([F:11])[F:10])=[O:4].C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([P:12](=[O:13])([OH:19])[OH:16])([F:11])[F:10])=[O:4]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCC(F)(F)P(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCC(F)(F)P(=O)(O)O)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl 4-((R)-2-amino-3-((R)-2,3-bis(dodecanoyloxy)propylthio)propanamido)-1,1-difluorobutylphosphonate (1 eq) in DCM (0.1 M) was added trimethylsilyl bromide (10 eq). The reaction mixture was stirred at room temperature overnight and concentrated. The crude mixture was purified by reverse phase high performance liquid chromatography (HPLC) with C4 column eluting with a gradient of 30-80% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to give the title compound as a white solid. 1H NMR (CDCl3): δ 8.74 (br s, 1H), 5.07-5.17 (m, 1H), 4.29 (dd, 1H), 4.19 (dd, 1H), 3.66-3.78 (m, 1H), 2.25-3.51 (m, 4H), 2.66-2.98 (m, 4H), 2.23-2.36 (m, 4H), 1.05-1.84 (m, 2H), 1.60-1.84 (m, 2H), 1.44-1.58 (m, 4H), 1.17-1.34 (m, 32H), 0.85 (t, 6H). LRMS [M+H]=731.4.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH3:15])[CH:2]=[CH2:3].S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9]([Cl:18])=[O:10])=[CH:7][C:6]=1[CH3:15])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(C)cc(C(=O)O)cc1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=CCOc1c(C)cc(C(=O)Cl)cc1C

Procedure:
To a solution of 4-allyloxy-3,5-dimethyl-benzoic acid (5.26 g, 25.5 mmol) in CHCl3 (75 mL), thionylchloride (7.5 mL, 103 mmol) is added at rt. The mixture is refluxed for 2 h before the solvent is evaporated to give crude 4-allyloxy-3,5-dimethyl-benzoic acid chloride as a brownish oil. To a solution of the acid chloride in DCM (50 mL), hydrazine (75 mL of a 1 M solution in THF) in DCM (250 mL) is added at 0° C. The mixture is stirred at rt for 15 h before it is diluted with diethyl ether and extracted with 1 N aq. HCl (75 mL, then 5×50 mL). The combined aq. extracts are basified by adding 33% aq. KOH solution and extracted with DCM (5×50 mL). The combined DCM extracts are dried over Na2SO4, filtered and evaporated to give 4-allyloxy-3,5-dimethyl-benzoic acid hydrazide (5.39 g) as a white solid; LC-MS: tR=0.71 min; [M+1]+=221.20; 1H NMR (D6-DMSO): δ 2.22 (s, 6H), 4.28-4.37 (m, 2H), 4.39 (s, 2H), 5.19-5.28 (m, 1H), 5.36-5.47 (m, 1H), 6.00-6.15 (m, 1H), 7.49 (s, 2H), 9.55 (s, 1H).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[F:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]([CH3:15])[C:13]#[N:14])[CH:11]=1>C(O)C>[F:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]([CH3:15])[C:13](=[NH:14])[O:1][CH2:2][CH3:3])[CH:11]=1
Reactant: CC(C#N)n1cc(F)cn1
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=N)C(C)n1cc(F)cn1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of sodium ethoxide, prepared by adding solid sodium metal (64.4 mg, 2.80 mmol) to ethanol (10 mL), was added a solution of 2-(4-fluoro-1H-pyrazol-1-yl)propanenitrile (390 mg, 2.80 mmol) in ethanol (2 mL). The reaction mixture was stirred at 70° C. for 18 h. The mixture was cooled to room temperature and used without further purification. MS (EI+) (M+) 186; GCMS retention time: 1.27 min (Method O).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O-:7])=[CH:3][CH:2]=1.[Na+].C1C=CC=CC=1.CN(C)C=O.[Cl:20][CH2:21][C:22]1[N:26]=[C:25](Cl)[S:24][N:23]=1>O>[Cl:20][CH2:21][C:22]1[N:26]=[C:25]([O:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[S:24][N:23]=1
Reactant: ClCc1nsc(Cl)n1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: ClCc1nsc(Oc2ccccc2)n1
Temperature: 20 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
5.8 g of sodium phenate were added to a mixture of 50 ml of benzene, 10 ml of dimethylformamide and 8.5 g of 3-chloromethyl-5-chloro-[1,2,4]-thiadiazole and the mixture was stirred at 20° C. for 24 hours. 50 ml of water were added to the mixture and the decanted aqueous phase was extracted with benzene. The combined organic phase was dried and evaporated to dryness. The oil residue was distilled under reduced pressure to obtain 7.2 g of 3-chloromethyl-5-phenoxy-[1,2,4]-thiadiazole boiling at 114°-116° C. at 0.5 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br>O.Br>[Br:12][C:7]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: BrBr
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Agent: Br
Solvent: O
Product: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.6 %

Procedure:
A solution of 4-fluoro-2-nitroaniline (39.03 g, 250 mmol) in water (900 mL) and 48% hydrobromic acid (1500 mL) was treated with bromine (15.26 mL, 46 g, 288 mmol) added dropwise over 20 min. The resulting precipitate was stirred at ambient temperature for a further 45 min then diluted with ice-water (2000 mL). The solid product was collected by filtration, washed with cold water and dried to afford 2-bromo-4-fluoro-6-nitrophenylamine as an orange powder (55 g, 94%): δH (360 MHz, CDCl3) 6.49 (2H, br), 7.56 (1H, dd, J 7 and 3), 7.90 (1H, dd, J 9 and 3).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.Cl.O1CCOCC1>>[NH2:7][C@@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[C:14]([CH3:21])([CH3:22])[C:13]2=[O:23])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2C(=O)C(C)(C)c3nccnc32)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)C(=O)N([C@H]2C[C@@H](N)C2)c2nccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottomed flask was added tert-butyl(cis-3-(7,7-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)cyclobutyl)carbamate (0.1812 g, 0.545 mmol) and hydrogen chloride, 4.0M solution in 1,4-dioxane (0.136 ml, 0.545 mmol, Sigma-Aldrich Chemical Company, Inc.) to stir at room temperature for 1 h. Solvent was evaporated and carried on without further purification. LCMS showed product peak at 0.357 min (m+=233.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 5 H) 2.61-2.74 (m, 2 H) 2.91-3.04 (m, 2 H) 3.63-3.76 (m, 1 H) 4.50-4.64 (m, 1 H) 8.18 (s, 2 H)
Reaction SMILES: I[C:2]1[CH:20]=[N:19][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:10](=[O:18])[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[N:21]1([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([C:34]3[CH:39]=[CH:38][C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][CH:35]=3)=[O:33])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:12]1([CH2:11][C:10]([N:9]2[CH2:8][CH2:7][NH:6][C:5]3[N:19]=[CH:20][C:2]([C:37]4[CH:38]=[CH:39][C:34]([C:32]([N:29]5[CH2:28][CH2:27][CH:26]([N:21]6[CH2:22][CH2:23][CH2:24][CH2:25]6)[CH2:31][CH2:30]5)=[O:33])=[CH:35][CH:36]=4)=[CH:3][C:4]2=3)=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cc1ccccc1)N1CCNc2ncc(I)cc21
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Product: O=C(c1ccc(-c2cnc3c(c2)N(C(=O)Cc2ccccc2)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 52 %

Procedure:
1-(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)-2-phenylethanone (30 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a white foam (52% yield). M.p. (foam), LCMS: m/z=510.13 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.47-1.62 (m, 2H), 1.75-2.05 (m, 3H), 2.22-2.29 (m, 1H), 2.53-2.62 (m, 5H), 2.82-3.10 (m, 3H), 3.33-3.52 (m, 2H), 3.71-3.88 (m, 3H), 3.95 (s, 2H), 4.51-4.63 (m, 1H), 5.25 (bs, 1H), 7.12-7.34 (m, 5H), 7.35-7.48 (m, 4H), 8.16 (s, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCOCC2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 15 g (120.86 mmol) of p-fluorobenzaldehyde in 200 ml of DMF, 16.8 g (193.4 mmol) of morpholine and 33.36 g (241.7 mmol) of potasium carbonate are added successively at r.t. After being stirred for 8 h at 100° C., the reaction mixture is cooled to r.t., diluted with ice water and then the mixture is extracted with AcOEt and CH2Cl2. The combined extracts are concentrated under reduced pressure and purified by silica gel column chlomatography (eluent: n-Hexane:AcOEt=5:1˜3:1) to give 4-morpholin-4-yl-benzaldehyde. 1H-NMR (400 MHz, CDCl3): 3.35–3.40 (m, 4H), 3.85–3.90 (m, 4H), 6.92 (d, 2H, J=8.56 Hz), 7.77 (d, 2H, J=8.56 Hz), 9.80 (s, 1H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH2:9]([N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]1[SH:23])[CH:10]=[CH2:11]>CN(C=O)C>[CH2:9]([N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]=[C:13]1[S:23][CH3:1])[CH:10]=[CH2:11]
Reactant: C=CCn1c(S)nc(C(F)(F)F)cc1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCn1c(SC)nc(C(F)(F)F)cc1=O
Yield: 79 %

Procedure:
Next, potassium carbonate (22.5 g, 163 mmol) and methyl iodide (10.2 ml, 164 mmol) were added to DMF (110 ml) solution of 3-allyl-2-mercapto-6-trifluoromethyl-4(3H)-pyrimidinone (32.1 g, 136 mmol) with stirring under ice-cooling, followed by stirring for 23 hours while gradually returning to room temperature. After completion of the reaction, the reaction solution was concentrated under a reduced pressure, saturated brine (100 ml), water (100 ml) and ethyl acetate (300 ml) were added to the thus obtained residue to separate the organic layer and then the aqueous layer was extracted with ethyl acetate (100 ml×2). The organic layers were combined, washed with saturated brine (50 ml×2) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. The thus obtained crude product was purified, by a silica gel column chromatography (hexane˜hexane:ethyl acetate=9:1) to obtain white solid of 3-allyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone (26.9 g, 79%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]([Cu])#[N:14]>CN1C(=O)CCC1.O>[C:13]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6])#[N:14]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a stirred solution of methyl 3-bromo-4-hydroxybenzoate (2.50 g, 10.775 mmol) in NMP (7.5 mL) was added CuCN (1.05 g, 11.853 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 200° C. for 4 h., cooled to RT, diluted with water (10 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford methyl 3-cyano-4-hydroxybenzoate (1.50 g, 78%) as a yellow solid.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH:14]2[CH:7]1[CH2:8][C:9]1([CH2:13]2)[CH2:12][O:11][CH2:10]1)=[O:5].[CH3:16][Mg]Br>O1CCCC1.[Cl-].N>[O:11]1[CH2:10][C:9]2([CH2:8][CH:7]3[CH:14]([CH:6]3[C:4](=[O:5])[CH3:16])[CH2:13]2)[CH2:12]1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1C2CC3(COC3)CC21
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)C1C2CC3(COC3)CC21
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To an ice-cooled solution of N-methoxy-N-methylspiro[bicyclo[3.1.0]hexane-3,3′-oxetane]-6-carboxamide (0.30 g, 1.4 mmol) in tetrahydrofuran (15 mL) was added methylmagnesium bromide (1 mL, 3M in tetrahydrofuran) dropwise. After 1 h, the reaction mixture was diluted with saturated aqueous ammonia chloride solution (10 mL), and the resulting solution was extracted with ethyl acetate (3×20 mL). The collected organic was concentrated to provide product as a brown oil (220 mg, 93% yield).
Reaction SMILES: [CH3:1][C:2]12[C:13]3[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:12]=3[CH2:11][CH:9]([NH:10]1)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].CN([CH:25]=[O:26])C.O>[Cu].CCOCC>[CH3:1][C:2]12[C:13]3[CH:14]=[C:15]([O:26][CH3:25])[CH:16]=[CH:17][C:12]=3[CH2:11][CH:9]([NH:10]1)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC12NC(Cc3ccc(Br)cc31)c1ccccc12
Reactant: CN(C)C=O
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)C1(C)NC(C2)c2ccccc21

Procedure:
A mixture of 0.00905 mol of 3-bromo-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, 0.181 mol of sodium methoxide, 5.56 g of electrolytic copper dust, and 87 ml of DMF is stirred and heated on a steam bath for 2.5 hours. After cooling, 150 ml of water and 150 ml of ether is added to the mixture, and, after stirring, the mixture is filtered through a pad of celite. The ether phase is separated, washed with water, dried over magnesium sulfate, filtered, and the ether is removed on a rotary evaporator. The residue is dissolved in warm acetonitrile. On standing, the solution deposits crystals. The supernatant, containing the desired product, is decanted from the crystals. Evaporation of the solvent gives 3-methoxy-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][CH2:8][P:9]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:10])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[K+].I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1COCC1>[C:4]([CH:6]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH3:28])[CH2:7][CH2:8][P:9](=[O:10])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)CCCP(=O)(OCC)OCC
Reactant: CCCCCCCCCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(CCP(=O)(OCC)OCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
A solution of triethyl 4-phosphonobutyrate (1.00 g, 3.96 mmol) in 1 mL of THF was added to potassium bis(trimethylsilyl)amide (0.5 M in THF, 8.70 ml, 4.36 mmol) at −78° C. After stirring for 1 h at −78° C., 1-iodododecane (1.2 mL, 4.75 mmol) was added dropwise. The reaction was removed from the bath, warmed to rt and stirred for 2 h. The reaction was diluted with ethyl acetate (50 ml), washed with 2 N HCl (50 mL), sat'd NaCl (50 mL), dried and concentrated. Flash chromatography using 3:1 v/v hexane/acetone afforded 610 mg of the title compound: ESI-MS 421.3 (M+H).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].Cl[C:5]1[N:10]=[C:9]([C:11]2[C:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:8]=[CH:7][CH:6]=1.[H-].[Na+]>CN(C=O)C.C(Cl)Cl>[CH2:1]([S:3][C:5]1[N:10]=[C:9]([C:11]2[C:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:8]=[CH:7][CH:6]=1)[CH3:2]
Reactant: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCSc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Yield: 91.5 %

Procedure:
Add ethanethiol (0.71 mL, 0.96 mmol) to a solution of 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (37 mg, 0.1 mmol) in DMF (2.5 mL) at 0° C. Add sodium hydride (38 mg, 0.96 mmol), stir the mixture at room temperature for 72 hours. Dilute the reaction mixture with methylene chloride (50 mL) and wash with water (2×50 mL), brine (1×50 mL). Dry the combined organic layers with sodium sulfate and concentrate. Purify the residue by flash column chromatography (SiO2, 50% ethyl acetate/hexanes) to give the title compound 35 mg (91%) as an off-white solid.
Reaction SMILES: [CH:1]1[C:10]2[C@@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[O:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>>[F:30][C:28]1[CH:27]=[CH:26][C:25]2[C:21]([CH2:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][C@@H:12]4[N:8]5[C:9]6[C:4](=[CH:3][CH:2]=[CH:1][C:10]=6[C@@H:11]4[CH2:16]3)[CH2:5][CH2:6][CH2:7]5)=[N:22][O:23][C:24]=2[CH:29]=1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc2c(CCCN3CC[C@H]4[C@@H](C3)c3cccc5c3N4CCC5)noc2c1
Yield: 79.2 %

Procedure:
The title compound (0.31 g, 75%) was prepared by the general method of Example 402 from (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.21 g, 1.0 mmol), 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole (0.43 g, 2.0 mmol), KI (catalytic) and K2CO3 (0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. The 1H NMR was identical to that of Example 408, (±)-cis-10-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11][OH:12])=[O:5])[CH3:2].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[O:9][C:10]=1[CH2:11][O:12][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1COC1CCCCO1
Temperature: 25 °C

Procedure:
4.8 g 5-Hydroxymethyl-2-(4-methoxy-phenyl)-oxazole-4-carboxylic acid ethyl ester were dissolved in 75 ml dichloromethane. 1.9 ml 3,4-dihydro-2H-pyran and 870 mg pyridinium p-toluenesulfonate were added and the reaction mixture stirred at room temperature over night. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel (eluting with n-heptane:ethyl acetate=3:1=>1:1) to obtain 5.3 g 2-(4-methoxy-phenyl)-5-(tetrahydro-pyran-2-yloxymethyl)-oxazole-4-carboxylic acid ethyl ester.