Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]12[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH:9]1[CH2:8][CH2:7][O:6][C:5]1[CH:18]=[C:19]([NH2:22])[CH:20]=[CH:21][C:4]2=1)[CH3:2].C1C(=O)N([Br:30])C(=O)C1>C1COCC1>[Br:30][C:20]1[C:19]([NH2:22])=[CH:18][C:5]2[O:6][CH2:7][CH2:8][CH:9]3[CH2:10][C:11]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:16][CH2:17][C:3]3([CH2:1][CH3:2])[C:4]=2[CH:21]=1
Reactant: CCC12CCC3(CC1CCOc1cc(N)ccc12)OCCO3
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCC12CCC3(CC1CCOc1cc(N)c(Br)cc12)OCCO3
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
A solution of rac-(7aR,11aS)-11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (86, R2=Ethyl) (11.2 g, 37.0 mmol) in THF (370 mL) was cooled to about −10° C. in a salt/ice bath and was then treated with NBS (6.59 g, 37.0 mmol) with stirring for about 5 min. The reaction was quenched by addition of sat. aq. NaHCO3 (250 mL), and the mixture was diluted with EtOAc (350 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine (350 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel (220 g, eluted with 0% to 40% EtOAc in heptane). Collection and concentration of the appropriate fractions gave rac-(7aR,11aS)-2-bromo-11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (87, R2=Ethyl) (13.6 g, 96%) containing about 20% of a minor regioisomer. The material was used directly in Step #4 without further purification. LC/MS, method 3, 2.49 min, MS m/z 382, 384 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([NH:7][NH2:8])=O.[CH3:13][N:14]=[C:15]=[S:16].C([O-])(O)=O.[Na+].Cl>CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:14]([CH3:13])[C:15](=[S:16])[NH:8][N:7]=2)[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CN=C=S
Reactant: NNC(=O)c1cc(F)cc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cn1c(-c2cc(F)cc(F)c2)n[nH]c1=S
Temperature: 70 °C

Procedure:
3,5-difluorobenzohydrazide (5 g, 29 mol) and methyl isothiocyanate (2.1 g, 29 mmol) were mixed in 2-propanol (100 ml) and heated to 70° C. o.n. The reaction was cooled to r.t. and the formed precipitate was filtered off. H2O (100 mL) and NaHCO3 (4 g, 48 mmol) were added to the solid and the mixture was heated to 70° C. for 2 h. The reaction mixture was cooled to r.t., acidified with concentrated HCl and the title compound, 6.4 g (97%), was collected by filtration. LC-MS (M++1): 228
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH2:31][C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 83.1 %

Procedure:
To a solution of 1.00 g (2.985 mmol) of the product of Example 3 in 7.5 mL of DMF was added 0.514 g (3.134 mmol) of 3-picolyl chloride hydrochloride and 1.30 g (9.50 mmol) of potassium carbonate. The rection was stirred for 18 h at room temre and then an additional 0.051 g of 3-picolyl chloride hydrochloride and 0.130 g of potassium carbonate was added and the reaction was steeed for 18 h at room temperature. The reaction was then diluted with water and extracted with ether. The combined organic layers were extrated with 6N HCl solution and the aqueous acid layer was then basified with 6N NaOH solution and then extracted with ether. The resulting ether layer was dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with ether provided 1.058 g (83%) of the desired product as a white solid. Electrospray Mass Spec: 427.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.[CH2:27]([N:34]([C:42]12[CH2:49][CH2:48][C:45]([CH:50]=[O:51])([CH2:46][CH2:47]1)[CH2:44][CH2:43]2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH2:27]([N:34]([C:42]12[CH2:47][CH2:46][C:45]([CH:50]([C:3]3[C:2]([Cl:1])=[CH:7][N:6]=[C:5]4[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:4]=34)[OH:51])([CH2:44][CH2:43]1)[CH2:48][CH2:49]2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C12CCC(C=O)(CC1)CC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C34CCC(N(Cc5ccccc5)C(=O)OC(C)(C)C)(CC3)CC4)c(Cl)cnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.6 %

Procedure:
To a solution of 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.33 g, 3.06 mmol, Adesis) in THF (25 mL) at about −78° C. was added n-BuLi (1.6 M solution in hexanes, 2.00 mL, 3.20 mmol) at such a rate that the internal temperature did not exceed about −70° C. The reaction mixture was stirred for about 45 min and a solution of tert-butyl benzyl(4-formylbicyclo[2.2.2]octan-1-yl)carbamate (1.05 g, 3.06 mmol) in THF (6 mL) was added dropwise. The reaction mixture was stirred at about −78° C. for about 1 h and was slowly warmed to ambient temperature and stirred for about 1 h. Saturated aqueous NH4Cl and EtOAc (10 mL each) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2×10 mL) and the combined organics were washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The remaining oil was purified by silica gel chromatography eluting with a gradient of 0-40% EtOAc in heptane to give tert-butyl benzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamate (1.27 g, 64%) as a clear colorless oil: LC/MS (Table 1, Method o) Rt=3.78 min; MS m/z: 652 (M+H)+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[N:9](OC)=O.N([O-])=O.[Na+].S(=O)(=O)(O)O>CO>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[N:9]1
Reactant: CON=O
Reactant: Nc1ccccc1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: c1ccc2[nH]nnc2c1
Temperature: 50 °C

Procedure:
108 g of freshly distilled 99.8% pure o-phenylenediamine were suspended in 125 ml of methanol and heated to 50° C. At this temperature, gaseous methyl nitrite, prepared from sodium nitrite solution (25% strength), methanol and sulphuric acid (48% strength), was introduced. The rate of addition was such that no off-gas left the reaction flask. As soon as the reaction mixture did not absorb any more gas (about 2 hours), a sample was removed and tested for complete conversion. This was followed by first distilling off methanol and then water from the reaction mixture. With the addition of polywax (polydiol 1550) as a lubricant, the mixture was then distilled continuously through a thin-film evaporator at 4 mbar and a heater temperature of 220° C. Benzotriazole came over at about 165° C. and 4 mbar. Such freshly distilled benzotriazole is 99.9% pure, as analyzed by gas chromatography. It has a slightly yellow colour. On standing for several weeks, the pale yellow colour fades to a palate beige colour.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: NCCc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: NCCc1cccc(O)c1
Yield: 95.4 %

Procedure:
10% Palladium-carbon catalyst (water content 50%, 86 mg) was added to a solution of 2-(3-benzyloxyphenyl)ethylamine (434 mg, 1.91 mmol, 1.0 eq) in THF (10 ml), and the mixture was stirred at room temperature for 3 hours in a stream of hydrogen. The reaction ma ire was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 2-(3-hydroxyphenyl)ethylamine (250 mg, 95.5%).
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[CH:8]=[C:9]([CH2:11][CH2:12][NH2:13])[N:10]=1)[CH2:3][CH2:4][CH3:5].[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH:33]=O.C(O)C>C(Cl)(Cl)Cl>[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]2[CH:33]([C:32]([O:36][CH2:37][CH3:38])=[O:35])[NH:13][CH2:12][CH2:11][C:9]=2[N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)C=O
Reactant: CCCCc1nc(CCN)cn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OCC)NCC2
Yield: 44.1 %

Procedure:
A mixture of 2-n-butyl-4-(2-aminoethyl)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole hydrochloride (0.278 g), ethyl glyoxylate (0.179 g) and ethanol (5 ml) is refluxed for three days. To the mixture is added chloroform, and the mixture is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=10:1) to give ethyl 2-n-butyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.136 g) as a foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:16][C:14]=1[NH2:15].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[CH:16][C:14]=2[NH2:15])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN(c2ccc(NS(=O)(=O)c3cccc(F)c3)c(N)c2)CC1
Yield: 56.5 %

Procedure:
A mixture of 2-nitro-3-chloroaniline (4.47 g, 25.9 mmol), methylpiperazine (3.1 g, 31 mmol) and K2CO3 (5.41 g, 39 mmol) in acetonitrile was stirred at 70° C. for 48 h. The mixture was filtered and purified by column chromatography (SiO2, CH2Cl2/MeOH/Heptane/NH3 4:1:5×0.2%) to give 1.6 g of product (unreacted starting material was isolated): 1H-NMR δ 7.66-7.45 (m, 5H), 6.78 (d, 1H), 6.62 (d, 1H), 6.50 (dd, 1H), 3.39-3.35 (m, 4H), 3.02-2.99 (m, 4H); MS (posES-FIA) m/z 333.0 (M++H). The product (1.06 g, 4.49 mmol) was dissolved in EtOH:THF (4:1). Raney-Ni and hydrazine (1.12 mL, 22 mmol) were added. The reaction was stirred at room temperature for 3 h until the yellow color disappeared. Filtration through wet Celite pad, followed by removal of the solvent afforded 0.802 g of 2-amino-5-(4-methyl-1-piperazinyl)aniline which was used without further purification in the next step. 3-Fluorobenzenesulfonyl chloride (0.133 g, 0.68 mmol) was added to a solution of 2-amino-5-(4-methyl-1-piperazinyl)aniline (0.141 g, 0.68 mmol) and pyridine (514 mL, 6.39 mmol) in CH2Cl2. After 1 h the mixture was washed with aq NaHCO3 (10%), dried (MgSO4) and the solvent was removed. Purification by chromatography (SiO2, CH2Cl2/methanol/heptane, 4:1:5) gave 3-fluoro-N-[2-amino-4-(4-methyl-1-piperazinyl)-phenyl]benzenesulfonamide (0.140 g, 57%). MS (posES-FIA) m/z=found: 365.2. calcd: 364.14. Anal. (C17H22ClFN4O2S.3H2O) C, H, N, S. The reaction produced a small amount of bis-sulfonylated compound 3-fluoro-N-[2-{[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)-phenyl]benzenesulfonamide (0.010 g, 3%). The products were transformed into their HCl-salt before analysis; MS (posES-FIA) m/z=found. 523.5. calcd: 522.12. Anal. (C23H25ClF2N4O4S2) C, H, N, S.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:5]([Br:24])=[CH:4][N:3]=1.[CH3:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:6]2[C:5]([Br:24])=[CH:4][N:3]=[C:2]3[NH:1][C:31]([C:30]4[CH:33]=[CH:34][C:27]([N:26]([CH3:35])[CH3:25])=[CH:28][CH:29]=4)=[N:8][C:7]=23)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
To tert-butyl 4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazine-1-carboxylate (0.5 g, 1.2 mmol) in EtOH (20 mL) was added 4-dimethylaminobenzaldehyde (0.241 g, 1.6 mmol), and 1M Na2S2O4 (4.7 mL, 4.7 mmol) The reaction mixture was stirred at 80° C. for 16 h then concentrated in vacuo. The residue was purified by chromatography (100% dichloromethane to dichloromethane/ethyl acetate 1/1, 2% MeOH in dichloromethane/ethyl acetate 1/1, and 2% MeOH in CHCl3). The compound is further triturated in dichloromethane/methanol 9/1, filtered and dried in vacuo to give the title compound as a solid (0.394 g, 63% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([CH2:21]O)[CH:18]=[C:19]([CH3:20])[C:14]=3[N:13]=[C:12]2[CH2:23][CH2:24][CH3:25])=[CH:6][C:5]=1[F:26].CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([CH2:21][N:42]=[N+:43]=[N-:44])[CH:18]=[C:19]([CH3:20])[C:14]=3[N:13]=[C:12]2[CH2:23][CH2:24][CH3:25])=[CH:6][C:5]=1[F:26]
Reactant: CCCc1nc2c(C)cc(CO)cc2n1Cc1ccc(C(=O)OC)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(CN=[N+]=[N-])cc2n1Cc1ccc(C(=O)OC)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
Intermediate (8a) (2.4 g, 6.5 mmol) was added to 125 mL of DCM followed by DIPEA (4.6 mL, 26.1 mmol) and 4-dimethylaminopyridine (80 mg, 653 μmol). Methanesulfonyl chloride (1.0 mL, 13.1 mmol) was then added at 0° C. and the mixture was warmed to room temperature. After 3 hours, the mixture was concentrated and the material redissolved in 40 mL DMF. Sodium azide (467 mg, 7.2 mmol) was added and the mixture was heated at 80° C. for 1 hour. The mixture was then cooled to room temperature. The solution was partitioned between EtOAc (100 mL) and 50 mL 10% LiCl (aqueous). The organic layer was concentrated and flash chromatographed 20-70% EtOAc:hexanes to yield Intermediate (8b) as a yellow oil (2.1 g). MS m/z: [M+H+] calcd for C21H22FN5O2, 396.2. found 396.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:22])[CH3:2]
Reactant: CCc1ccccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1CC
Temperature: 60 °C
Yield: 81.9 %

Procedure:
To a stirred solution of 2-ethylphenol (5ml, 42.4mmoles, 1eq) in dry DMF (120ml, 0.35M) was added potassium carbonate (6.45g, 46.6mmoles, 1.1eq) and ethylbromoacetate (4.7ml, 42.2mmoles, 1eq) and heated to 60° C. overnight. After cooling to room temperature the reaction mixture was partitioned between ethyl ether and 1N NaOH. The phases were separated and the organic portion washed twice with 1N NaOH, twice with H2O, brine, dried over Na2SO4, filtered and concentrated in vacuo to yield 7.2g (82%) of product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F:29][C:30]([F:35])([F:34])[C:31]([CH3:33])=[O:32]>O1CCCC1>[C:13]([C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:31]([OH:32])([CH3:33])[C:30]([F:35])([F:34])[F:29])=[CH:25][CH:26]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)C(F)(F)F
Reactant: C#Cc1ccc(C(=O)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(C#Cc1ccc(C(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (99 mL, 0.87 mmol) in freshly distilled tetrahydrofuran (5 mL) was added a solution of n-butyllithium (326 mL of a 2.5M solution in hexanes, 0.81 mmol). The solution was stirred at -78° C. for 25 minutes before a tetrahydrofuran solution of 4-benzoylphenylethyne (120 mg, 0.58 mmol) was added. The reaction was kept at -78° C. for an additional 20 minutes before 1,1,1-trifluoroacetone (521 mL, 5.8 mmol) was added in one portion. After stirring at -78° C. for 15 minutes the reaction was quenched by pouring into a saturated NH4C1 solution. The product was extracted into diethyl ether. The combined ethers were dried and evaporated. The crude product was adsorbed onto silica gel and purified by chromatography, with ethyl acetate:hexanes as the eluent (gradient 1:9 to 1:3), to yield the title compound as a white solid after trituration with hexanes (80 mg, 43%); mp 94.5°-96.0° C.; 250 MHz NMR (CDCl3): 1.76 (s,3, CH3), 2.88 (s,1, OH), 7.46-7.64 (m,5, Ar), 7.77-7.79 (m,4, Ar); MS: m/z=319(M+ 1). Analysis for C18H13F3O2 : Calculated: C, 67.92; H, 4.14; Found: C, 68.16; H, 4.15.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][C:38]=1[O:45][CH3:46]>C1COCC1.O>[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[CH:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:39][C:38]=1[O:45][CH3:46]
Reactant: COc1cc(C=O)ccc1F
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=CCC(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
To a solution of (2-carboxyethyl)triphenylphosphonium bromide (14.8 g, 35.7 mmol) in THF (40 mL) was added NaHMDS (35.8 mL, 71.5 mmol) at −20° C., and the reaction was stirred for 20 min. 4-Fluoro-3-methoxybenzaldehyde (5.0 g, 32.5 mmol) was added to the reaction at −78° C., and the reaction was stirred overnight while warming to rt. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). Organics were washed with brine (30 mL), dried (Na2SO4), and concentrated to give 6.0 g (88%) of the crude title compound as a yellow solid. [M+H] Calc'd for C11H11FO3, 211. Found, 211.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([OH:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH2:18][CH3:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Product: CCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and ethanol. Light brown solid. MS (m/e): 208.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [NH2:1][NH2:2].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.O>CO>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]([NH:1][NH2:2])=[O:4])=[CH:8][CH:9]=1
Reactant: NN
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: CO
Solvent: O
Product: NNC(=O)Cc1ccc(O)cc1
Temperature: 52.5 °C
Reaction time: 1 h

Procedure:
Neat anhydrous hydrazine 21.0 g (654 mmol) was added to a solution of p-hydroxyphenylacetic acid methyl ester 27.18 g (163.5 mmol) in MeOH (100 mL) and the mixture was heated to 50-55° C. and stirred at this temperature for 90 min (water bath). Cooled, stirred for extra 1 hour, the precipitate collected by filtration, compressed on the frit, washed with MeOH (3×10 mL) and dried on high vacuum. A second fraction was obtained by cooling the supernatants to −15° C. overnight and filtering the formed precipitate.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)#[N:2].Cl.[NH2:9][OH:10].C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1](=[N:9][OH:10])[NH2:2]
Reactant: NO
Reactant: N#Cc1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1cccs1
Yield: 78.8 %

Procedure:
To a solution of 21.8 g (0.20 mole) of 2-cyanothiophene in 500 ml of ethanol, 13.9 g (0.20 mole) of hydroxylamine HCl is added, followed by the addition of 13.8 g (0.10 mole) of K2CO3 in 50 ml of water. The mixture is refluxed for 16 hours, cooled and diluted with 200 ml of water. After removing the ethanol in vacuo, the product precipitates out of the aqueous residue. It is collected by filtration, washed with water and dried to yield 22.4 g (80%) of product, m.p. 70°-75°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH2:25])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15].C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:37]=1[C:38](Cl)=[O:39]>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH:25][C:38]([C:37]1[C:36]([Cl:35])=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:45])=[O:39])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(Cl)cccc2Cl)C(F)(F)F)cnn1-c1ccc(F)cc1
Temperature: 21 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.93 g, 2.57 mmol) in anhydrous tetrahydrofuran (12 ml) was added diisopropylethylamine (0.91 ml, 5.2 mmol) followed by 2,6-dichlorobenzoyl chloride (0.38 ml, 1.05 equiv). There was an immediate exotherm and therefore the mixture was placed in an ice/solid carbon dioxide bath for 20 minutes and then stirred at 21° C. for 17 hours. It was then partitioned between ethyl acetate (100 ml) and 2M hydrochloric acid (20 ml) and the organic phase was washed with water (20 ml), saturated brine (20 ml), saturated sodium bicarbonate (20 ml), water (20 ml) and saturated brine (20 ml) before being dried over magnesium sulphate and evaporated under reduced pressure to give a foam. This was purified on a Flashmaster column of silica (100 g) with a gradient of 0-100% ethyl acetate in cyclohexane over 60 minutes to give the title compound (1.07 g).