Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18])([O-:8])=[O:7].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][C:3](=[O:4])[CH2:2][Br:1])([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C(Br)CBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CBr)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Under argon atmosphere bromo-acetyl bromide (2.67 mL, 30.66 mmol) dissolved in DCM (15 mL) was added within 15 min to a mixture of 2,4-dinitro-phenol (5.13 g, 27.88 mmol) and pyridine (2.92 mL, 36.24 mmol) in DCM (40 mL) at 0° C. After 1 h at RT, aqueous citric acid solution (10%, 30 mL) was added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue recrystallized from diethyl ether (75 mL) to afford the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:26]2[CH:27]=[CH:28][C:23]([OH:29])=[CH:24][CH:25]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C2(O)CCCN(Cc3ccccc3)C2)c1
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1cccc(C2(c3ccc(O)cc3)CCCN(Cc3ccccc3)C2)c1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a solution of 1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-ol (17.6 g, 73.1 mmol) in (CH2)2Cl2 (200 mL) was added phenol (16.7 g, 178 mmol) followed by portionwise addition (highly exothermic) of AlCl3 (23.3 g, 178 mmol). The reaction mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature and was slowly poured into a mixture of crushed ice (50 mL) and 30% aq. NH4H (120 mL). The mixture was stirred vigorously for 20 mininutes and was then filtered through celite. The celite cake was washed with CH2Cl2 (200 mL). The organic layer was separated and the aqueous layer was washed with CH2Cl2 (3×100 mL). The combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography with hexanes/EtOAc (1:1) to afford 16.3 g of 4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenol 1HNMR (400 MHz, CDCl13) δ 7.39-7.21 (comp, 5H), 7.19-7.05 (comp. 3H), 6.84 (s, 1H), 6.79 (d, 1H), 6.67-6.61 (comp, 3H), 3.73 (s, 3H), 3.50 (s, 2H), 2.86-2.79 (comp, 2H), 2.45-2.38 (comp, 2H), 2.21-2.19 (comp, 2H), 1.60-1.51 (comp, 2H); MS (M+1) 374.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][C:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[CH:27])=[CH:18][C:17]=1[CH3:28])([CH3:14])[C:11]([OH:13])=[O:12].C(N(CC)CC)C>C(#N)C.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C:27]#[C:26][CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:10]([CH3:14])([CH3:9])[C:11]([OH:13])=[O:12])=[C:17]([CH3:28])[CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(I)c1
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)O)c(C)c1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OCCCC#Cc2cccc(F)c2)ccc1OC(C)(C)C(=O)O
Reaction time: 2.5 h
Yield: 67.5 %

Procedure:
A degassed (argon) solution of 0.098 g (0.44 mmol) 1-fluoro-3-iodobenzene in 4 ml acetonitrile was treated with 0.111 g (0.40 mmol) 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid (example 26B]), 0.014 g (0.02 mmol) PdCl2(Ph3P)2, 0.004 g (0.02 mmol) of CuI and 0.17 ml (1.20 mmol) triethylamine. The reaction was stirred for 2.5 h and then extracted with chilled aqueous 10% KHSO4/ether (three times). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification was done by flash-chromatography on silica gel (1. n-heptane/EtOAc 4:1 and 2. CH2Cl2/MeOH 2%-10%). The pure fractions were evaporated, dissolved in ether and washed with aqueous 10% KHSO4/ether (three times). The organic phase was dried (Na2SO4) and evaporated to yield 0.10 g of the title compound as an orange viscous oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[BrH:19].BrBr>C(O)(=O)C>[Br:19][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:11]
Reactant: CSc1ccc(CC(=O)c2ccc(C)cc2)cc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CSc1ccc(C(Br)C(=O)c2ccc(C)cc2)cc1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
A 500 mL round-bottomed flask equipped with a pressure-equalizing addition funnel and provisions for magnetic stirring was charged with 2-(4-methylthiophenyl)-1-(4-methylphenyl)ethanone from Step 2 (10.0 g, 39.0 mmol), 33% HBr in acetic acid (70 mL) and glacial acetic acid (100 mL). Over approximately 20 minutes, a solution of bromine in acetic acid (1M, 39 mL) was added to the suspension, and the reaction was held at room temperature for one hour. Any undissolved solids were removed by filtration, and the reaction was concentrated in vacuo, to a residue. The residue was dissolved in methylene chloride (100 mL), washed with 5% Na2S2O5 (2×100 mL), dried over MgSO4, filtered, and concentrated in vacuo to a colorless oil. The oil was held under vacuum for 16 hours, yielding 2-bromo-2-(4-methylthiophenyl)-1-(4-methylphenyl)ethanone (8.38 g, 64%) as a dirty white solid: mp 97°-98° C. 1H NMR (CDCl3) 300 MHz 7.86 (d, J=8.46 Hz, 2H), 7.80(d, J=8.26 Hz, 2H), 7.33-7.16(m, 4H), 5.88(s, 1H), 2.43(s, 3H), 2.36(s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:14]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC#CCBr
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCCC#CCOc1ccc2ccc(=O)oc2c1

Procedure:
A solution of 7-hydroxycoumarin (0.324 g, 1.99 mmol) and 1-bromo-2-octyne (0.378 g, 1.99 mmol) in 200 ml of acetone was heated under reflux in the presence of anhydrous potassium carbonate (3 grams) for 24 hours. After the reflux period, the reaction mixture was cooled, filtered and the collected solid was washed with fresh acetone. The acetone washings and the filtrate were combined and the solvent evaporated under reduced pressure to yield a pale yellow viscous liquid. The crude product was dissolved in a minimum amount of ethyl acetate and petroleum ether added until the solution became cloudy. The cloudy solution was concentrated under reduced pressure and a white precipitate formed. This precipitate was collected by vacuum filtration and recrystallized from aqueous methanol to yield the title compound as shiny, colorless plates, m.p. 74°-75° C., 0.245 g, 50%. 1H-NMR: 0.8-2.2 (m, 11H, (CH2)4CH3), 4.7 (t, 2H, OCH2C C), 6.2 (d, 1H, C3 --H J=9.3 Hz), 6.8 (dd, 1H, C6 --H), 6.9 (d, 1H, C8 --H, J=2.1 Hz), 7.4 (dd, 1H, C5 --H, J=8.1 Hz), 7.6 (d, 1H, C4 --H, J=9.3 Hz).
Reaction SMILES: [CH3:1][C:2](=O)[C:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([C:18](=[O:22])[CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH:4]=1.[Cl-].[OH:25][NH3+:26].N1C=CC=CC=1>O>[N:26](=[C:2]([C:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([C:18](=[O:22])[CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH:4]=1)[CH3:1])[OH:25]
Reactant: [NH3+]O
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Product: CC(=NO)C1=CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 8 h

Procedure:
A mixture of 5α-pregna-2,16-diene-11,20-dione (60 g), hydroxylammonium chloride (21 g) and anhydrous pyridine (240 ml) was left to stand at room temperature overnight before diluting with ice and water. The precipitate obtained was collected by filtration, washed with water and dried in vacuo at 80° (62 g.). Crystallisation from ethyl acetate afforded the title compound, m.p. 168°-182°, [α]D +137°.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)[C:7]3[N:8]([C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=3)[CH:9]=2)[CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)[C:7]3[N:8]([C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cnc2c(-c3cnco3)cc(C3CC3)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c(-c3cnco3)cc(C3CC3)cn12
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 103.1 %

Procedure:
To a mixture of ethyl 6-cyclopropyl-8-(1,3-oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylate (150 mg) in a mixed solvent of THF (3 mL) and ethanol (1.2 mL) was added 8N aqueous sodium hydroxide solution (95 μL), and the mixture was stirred at 70° C. for 50 min. The reaction mixture was neutralized with 6N hydrochloric acid in an ice bath, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title Compound (140 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=2)=[CH:4][N:3]=1.[Se](=O)=[O:23]>O1CCOCC1>[CH:1]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=2)=[CH:4][N:3]=1)=[O:23]
Reactant: Cc1ncc(Oc2ccc(C(N)=O)cn2)c2ccccc12
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: NC(=O)c1ccc(Oc2cnc(C=O)c3ccccc23)nc1
Temperature: 80 °C

Procedure:
To 6-(1-methylisoquinolin-4-yloxy)nicotinamide (Preparation 19) (135 mg, 0.48 mmol) in dioxane (6 mL) under argon was added selenium dioxide (54 mg, 0.48 mmol). The mixture was heated to 80° C. for 3 h after which time selenium dioxide (54 mg, 0.48 mmol) was added. After a further 0.5 h at 80° C. the mixture was cooled, filtered through Celite and washed with EtOAc (50 mL). The organic phase was washed with NaHCO3 (30 mL), water (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo to give the title compound: RT=2.93 min; m/z (ES+)=294.1 [M+H]+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[CH:25]=[C:24]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[C:30]([CH3:39])([CH3:38])[CH2:29]2)=[O:27])[CH:23]=[C:22]([O:40][CH3:41])[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:24]1[CH:23]=[C:22]([O:40][CH3:41])[N:21]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:25]=1)=[O:27])[CH2:29][C:30]2([CH3:39])[CH3:38]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: COc1cc(C(=O)N2CC(C)(C)c3cc(F)ccc32)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)N2CC(C)(C)c3cc(F)ccc32)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1

Procedure:
0.26 g (0.9 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride, 0.30 g (0.9 mmol) (2-chloro-6-methoxy-pyridin-4-yl)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-methanone and 0.37 g (2.7 mmol) potassium carbonate were stirred in 3 mL NMP for 12 h at 130° C. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:29])([CH3:28])[C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].C1COCC1.[OH-].[Na+]>CO>[OH:27][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:16]1([CH3:28])[CH3:29]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 6.6 %

Procedure:
3β-Hydroxy-4,4-dimethylchola-5,7-dien-24-oic acid methyl ester (120 mg) is saponified in a mixture of 15 ml of methanol, 15 ml of THF and 0.7 ml of 1M sodium hydroxide at 50° C. After aqueous work-up and crystallisation from methanol, the title compound (7.6 mg) is isolated. Melting point: 210-213° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][N:10]([S:12]([C:15]2[CH:36]=[CH:35][C:18]3[N:19]([CH2:26][CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:21][C:17]=3[CH:16]=2)(=[O:14])=[O:13])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:22]([C:20]1[N:19]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30]([F:33])([F:34])[CH2:29][CH2:28]2)[C:18]2[CH:35]=[CH:36][C:15]([S:12]([N:10]3[CH2:9][CH:8]([NH2:7])[CH2:11]3)(=[O:14])=[O:13])=[CH:16][C:17]=2[N:21]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N)C3)ccc2n1CC1CCC(F)(F)CC1

Procedure:
Following the same procedure in Example 37, Step A, using tert-butyl[1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)azetidin-3-yl]carbamate (0.34 g, 0.63 mmol) and TFA (5 mL) in CH2Cl2 (10 mL). Yield: 0.26 g (93%). 1H NMR (400 MHz, METHANOL-D4) δ 1.47-1.57 (m, 2 H), 1.61 (s, 9 H), 1.63-1.84 (m, 4 H), 1.98-2.13 (m, 2 H), 2.16-2.32 (m, 1 H), 3.79-3.90 (m, 3 H), 3.97-4.08 (m, 2 H), 4.45 (d, J=7.42 Hz, 2 H), 7.75-7.84 (m, 1 H), 7.86-7.92 (m, 1 H), 8.14 (d, J=1.37 Hz, 1 H); MS (ESI) (M+H)+=441.3; Anal. Calcd for C21H30F2N4O2S+2.10 TFA (680.01): C, 44.51; H, 4.76; N, 8.24. Found: C, 44.48; H, 4.65; N, 8.43.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:2].[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C=Cc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A flame-dried 200 mL round bottomed flask was charged with 3-(2-formyl-4-hydroxyphenyl)acrylic acid tert-butyl ester (10.0 g, 40.3 mmol), tert-butylchlorodiphenylsilane (12.6 mL, 48.3 mmol), and dry CH2Cl2 (150 mL). Triethylamine (11.2 mL, 80 mmol) and N,N-dimethylaminopyridine (1.0 g, 1.0 mmol) were added, and the mixture was stirred at ambient temperature under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with additional CH2Cl2, washed with brine (2×), dried (Na2SO4), and concentrated to an oil. The crude product was purified using the Biotage medium pressure chromatography system (EtOAc:hexanes 5:95) to give a pale yellow oil (18.3 g, 93%). 1H NMR (400 MHz, CDCl3) δ 1.12 (s, 9H), 1.51 (d, J=15.1 Hz, 9H), 6.15 (d, J=5.1 Hz, 1H), 6.87 (dd, J=8.6, 2.7 Hz, 1H), 7.34-7.47 (m, 7H), 7.68-7.73 (m, 5H), 8.28 (d, J=15.6 Hz, 1H), 10.1 (s, 1H). MS (ES) m/e 487 (M+1).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1>CN(C)C=O>[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1ccncc1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccncc1
Yield: 71.4 %

Procedure:
A mixture of 74 g (0.5 mole) of phthalic anhydride, 60 g (0.56 mole) of 4-pyridinemethylamine and 200 mL of dimethylformamide was heated under reflux for 2 hours. The cooled mixture was filtered and the solids were washed with ether and dried to give 85.1 g of 2-(4-pyridinylmethyl)-1H-isoindole-1,3(2H) -dione, m.p. 164°-165°. Another 24.0 g was obtained by crystallization of the concentrated mother liquors from dimethylformamide. Combined yield: 99.1 g (83%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(O)(=O)C.[F:12][C:13]1[CH:28]=[CH:27][C:16]([C:17]([N:19]([CH3:26])[C@@H:20]([CH:23]([CH3:25])[CH3:24])[CH:21]=O)=[O:18])=[CH:15][C:14]=1[CH3:29].[Na].[OH-].[Na+]>C(Cl)Cl>[F:12][C:13]1[CH:28]=[CH:27][C:16]([C:17]([N:19]([C@@H:20]([CH:23]([CH3:24])[CH3:25])[CH2:21][N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)[CH3:26])=[O:18])=[CH:15][C:14]=1[CH3:29]
Reactant: OC1CCNCC1
Reactant: Cc1cc(C(=O)N(C)[C@H](C=O)C(C)C)ccc1F
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)[C@H](CN2CCC(O)CC2)C(C)C)ccc1F
Reaction time: 3 h
Yield: 21.5 %

Procedure:
Piperidin-4-ol (0.048 g, 0.48 mmol) and acetic acid (0.032 mL, 0.56 mmol) was added to (S)-4-fluoro-N,3-dimethyl-N-(3-methyl-1-oxobutan-2-yl)benzamide (Compound A2.1) (0.1 g, 0.40 mmol) in DCM (3 mL). The resultant mixture was stirred at rt for 30 min before sodium triacetoxyhydroborate (0.101 g, 0.48 mmol) was added. The stirring was continued at rt for 3 h. NaOH (1 N aq.) was added to the mixture. The organic phase was filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The product containing fractions was concentrated and the residue was purified a second time by preparative HPLC using Chiralpak AD 5 μm 20×250 mm column and Heptan/EtOH/TEA 80/20/0.1, as mobile phase to give the title compound (29 mg, 22%). Enantiomeric excess: 99.9%. Mixture of rotamers: (600 MHz, CD3OD) δ 0.82-1.08, 1.43-1.63, 1.71-2.06, 2.12-2.51, 2.54-2.81, 2.89, 2.97-3.09, 3.27-3.46, 3.51-3.65, 4.40-4.59, 7.06-7.14, 7.22-7.37. Total no of protons: 28. HRMS (M+H)+: calculated 337.2291. found 337.2268.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[O:25]([C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1nsnc1-c1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Oc2nsnc2-c2ccccc2)cc1
Temperature: 120 °C
Yield: 898.8 %

Procedure:
Under a dry nitrogen atmosphere 4.1 g (0.0021 mole) of 3-chloro-4-phenyl-1,2,5-thiadiazole was added to a stirred mixture of 3.73 g (0.0027 mole) of potassium carbonate and 2.4 g (0.0026 mole) of phenol in 50 ml of N,N-dimethylformamide. After complete addition the mixture was heated at 120° C. for 21 hours. The mixture was cooled, poured into 400 ml of ice water and the mixture extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography on silica gel, eluted with n-hexane:methylene chloride (1:1) to yield 4.8 g of 3-phenoxy-4-phenyl-1,2,5-thiadiazole, Compound 38 of Table I.
Reaction SMILES: Br.Br.[CH3:3][N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][NH:7]2.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:3][N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]
Reactant: CN1C[C@@H]2C[C@H]1CN2
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1N1C[C@@H]2C[C@H]1CN2C

Procedure:
Alternatively, a heterogeneous mixture of (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane 2HBr salt (0.544 g, 2 mmol), 2-fluoro-5-nitrotoluene (0.310 g, 2 mmol) and DIPEA (0.387 g, 6 mmol) in NMP was refluxed for 2 days. The resulting residue was purified by column chromatography (silica gel, hexanes then 5-10% EtOAc in hexanes to afford 2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-5-nitrotoluene, which was reduced by hydrogenation (H2, 10% Pd/C, MeOH, 40 PSI) to afford 3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline; LCMS: purity: 91%; MS (m/e): 218 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH2:9]1[O:11][C@H:10]1[CH2:12][OH:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][C@H:10]([OH:11])[CH2:12][OH:13])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: OC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(C[C@H](O)CO)c1
Yield: 18.1 %

Procedure:
3-Nitro-1-H-pyrazole (27) (600 mg, 5.3 mmol), (S)-glycidol (702 μL, 10.6 mmol) and K2CO3 (1.1 g, 8.0 mmol) in acetonitrile (7 mL) were heated in the microwave at 100° C. for 1 h. The solvent was evaporated in vacuo and the residue dissolved in ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer further extracted with ethyl acetate (10×20 mL). The organics were combined, dried over MgSO4, filtered and evaporated to give a crude oil. This was purified by flash chromatography on silica eluting with a gradient of 70% ethyl acetate/isohexane to ethyl acetate, to give the desired compound as a white solid (180 mg, 18%); LCMS, Rt=0.98 min (MeOH-FA method), m/z 188 (MH+).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[NH2:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1>ClCCl>[C:8]([NH:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=[O:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.76 ml, 5.45 mmol) and acetic anhydride (0.43 ml, 4.56 mmol) were added to an ice-cooled solution of tert-butyl 3-(aminomethyl)-1-azetidinecarboxylate (J. Med. Chem. 2001; 44(1); 94) (850 mg, 4.56 mmol) in dichloromethane (50 ml), and the reaction stirred for 30 minutes. The solution was washed with water (50 ml), brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate as eluant to afford the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:18])[C:16]#[CH:17].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:18][CH2:15][C:16]#[CH:17])[N:3]=[CH:4][N:5]=1
Reactant: C#CCO
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
In 5 ml of N,N-dimethylformamide were dissolved 212 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 68 mg of 2-propyn-1-ol, to which 49 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 170 mg of 4-(2-fluorophenyl)-6-(2-propynyloxy)pyrimidine (the present compound (54)).