Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:37]1[CH:38]=[CH:39][C:40]2[C:41]3[N:50]([CH2:51][CH:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)[C:49]([CH2:58][CH3:59])=[N:48][C:42]=3[C:43]([NH2:47])=[N:44][C:45]=2[CH:46]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.C(#N)C>[CH2:58]([C:49]1[N:50]([CH2:51][CH:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[C:41]2[C:40]3[CH:39]=[CH:38][C:37]([CH:2]=[CH:1][S:3]([CH3:6])(=[O:5])=[O:4])=[CH:46][C:45]=3[N:44]=[C:43]([NH2:47])[C:42]=2[N:48]=1)[CH3:59]
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Reactant: C=CS(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c2n1CC1CCOCC1
Temperature: 120 °C
Yield: 59.4 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (7 mg, 0.03 mmol), acetonitrile (15 mL), N,N-dimethylformamide (15 mL), methyl vinyl sulfone (150 mg, 1.41 mmol), triethylamine (0.53 mL, 3.8 mmol), tri-o-tolylphosphine (23 mg, 0.08 mmol) and 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (500 g, 1.28 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath for 16 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The resulting solid was partitioned between chloroform (100 mL) and 1% aqueous sodium carbonate (100 mL). The fractions were separated and the aqueous fraction was extracted with chloroform (2×50 mL). The combined organic fractions were sequentially dried (MgSO4), filtered, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-15% CMA over 1200 mL followed by 15-20% CMA over 1100 mL). Recrystallization from methanol provided 315 mg of 2-ethyl-7-[2-(methylsulfonyl)ethenyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)CCC.[Br:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>C1COCC1>[Br:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]([C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[OH:18]
Reactant: Cc1cccc(C=O)c1Br
Reactant: Ic1cnccn1
Agent: CCCC[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccc(C(O)c2cnccn2)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-iodopyrazine (0.48 mL, 4.85 mmol) in dry THF (3 mL) was brought to 0° C. followed by the slowly addition of butylmagnesium chloride, 2.0M solution in THF (2.4 mL, 4.85 mmol). The resulting dark solution was stirred at 0° C. for 30 min then a solution of 2-bromo-3-methylbenzaldehyde (1.06 g, 5.34 mmol) in THF (2 mL) was slowly added and kept at 0° C. for 2 h. The mixture was quenched with saturated NH4Cl and extracted with DCM. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography using gradient 1:1 hexanes/EtOAc to afford a yellow-orange oil as (2-bromo-3-methylphenyl)(pyrazin-2-yl)methanol.
Reaction SMILES: N[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.C=O.[C:26]([BH3-])#[N:27].[Na+].[C:30](O)(=O)C>C(#N)C>[Cl:23][C:4]1[CH:3]=[C:2]([N:27]([CH3:26])[CH3:30])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20]
Reactant: [BH3-]C#N
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (100 mg) was dissolved in acetonitrile (1 ml), and a 37% aqueous formaldehyde solution (0.123 ml) and sodium cyanoborohydride (29 mg) were added, and the mixture was stirred at room temperature for 1 hr. Then, a 37% aqueous formaldehyde solution (0.123 ml) and sodium cyanoborohydride (29 mg) were added, and acetic acid was added to neutralize the reaction mixture, which was followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ice water was added to the residue. A saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, dried and filtrated. The filtrate was concentrated under reduced pressure. Hexane was added to the residue and the precipitated pale-yellow crystals were washed, filtered, and dried under reduced pressure to give the objective compound (97 mg).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]#[C:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[CH:37][CH:36]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ccccc1C#Cc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(C#Cc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
189 d) N-Methyl-N-(2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl}-phenyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl)-phenyl]-N-methyl-methanesulfonamide (125.0 mg, 0.3464 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (73.0 mg, 0.382 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (37.0 mg, 0.0677 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.138 g, 77%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.40 (d, J=6.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.55-7.48 (m, 3H), 7.43 (t, J=7.5 Hz, 1H), 7.37 (t, J=7.5 Hz, 1H), 7.00 (d, J=7.7 Hz, 2H), 6.86 (t, J=7.0 Hz, 1H), 6.73 (s, 1H), 3.61 (s, 3H), 3.23-3.16 (m, 7H), 2.63-2.58 (m, 4H), 2.37 (s, 3H). MS=516 (MH)+.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.22 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as an off-white solid (0.21 g, 51% yield), mp=118–120° C.; MS (+) ESI m/z=402 (M+H)+, [α]D25=−23.7° (c=1, EtOH).
Reaction SMILES: [CH2:1]([C:3]1[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][C:17]2[CH2:16][CH2:15][CH:14]3[CH:6]([CH2:7][CH2:8][C:9]4([CH3:25])[CH:13]3[CH2:12][CH2:11][C:10]4=[O:24])[C:5]=2[CH:4]=1)[CH3:2].CO.[BH4-].[Na+]>C1COCC1>[CH2:1]([C:3]1[C:19]([O:20][CH2:21][O:22][CH3:23])=[CH:18][C:17]2[CH2:16][CH2:15][CH:14]3[CH:6]([CH2:7][CH2:8][C:9]4([CH3:25])[CH:13]3[CH2:12][CH2:11][CH:10]4[OH:24])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(cc1OCOC)CCC1C2CCC2(C)C(=O)CCC12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc2c(cc1OCOC)CCC1C2CCC2(C)C(O)CCC12
Yield: 86.6 %

Procedure:
To a stirred, rt, solution of 2-Et-3-O-MOM estrone 52 (743 mg, 2.18 mmol) in THF (10 mL)/methanol (40 mL) solution was added sodium borohydride (76 mg, 2 mmol). After one hour the reaction was quenched by addition of ammonium chloride (2 mL of saturated solution), diluted with ethyl acetate (50 mL) and water (25 mL), the organic layer separated and washed with water, brine, dried and evaporated. Column chromatography (hexane/ethyl acetate gradient) gave the desired alcohol 53 as a clear colourless oil (650 mg) which showed δH (400 MHz, CDCl3, ref. TMS=0) 7.09 (1H, s, ArH), 6.78 (1H, s, ArH), 5.17 (2H, s, OCH2), 3.69-3.78 (1H, m, CHOH) 3.48 (3H, s, OMe), 2.78-2.86 (2H, m, 6-CH2), 2.61 (2H, q, J 7.4, CH2Me), 1.24-2.38 (13H, m), 1.19 (3H, t, J 7.4, CH2Me) and 0.77 (3H, s, 18-CH3).
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]=O)[N:15]3[CH3:18])=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:10]=2)[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[NH:31]1[CH2:34][CH:33]([N:35]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:31]4[CH2:34][CH:33]([N:35]5[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]5)[CH2:32]4)[N:15]3[CH3:18])=[C:11]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:10]=2)[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:2])[CH3:3]
Reactant: OC1CCN(C2CNC2)CC1
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(O)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.150 g, 0.37 mmol), 1-azetidin-3-ylpiperidin-4-ol (0.069 g, 0.44 mmol) and 4 Å molecular sieves (0.37 g) in DCE (3 mL) was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (0.157 g, 0.74 mmol) was added and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM, gradient 0:100 to 20:80) to give 550 as a white solid (0.137 g, 68%). LCMS (Method I): RT=2.41 min, [M+H]+ 546.3. 1H NMR (400 MHz, DMSO-d): δ 7.90-7.85 (m, 1 H); 7.66-7.61 (m, 1 H); 7.25-7.21 (m, 2 H); 4.53 (d, J=4.1 Hz, 1 H); 4.28-4.23 (m, 4 H); 3.96-3.86 (m, 1 H); 3.86 (s, 2 H); 3.85-3.68 (m, 7 H); 3.48-3.43 (m, 1 H); 3.42 (t, J=6.5 Hz, 2 H); 2.95 (t, J=6.5 Hz, 2 H); 2.90-2.82 (m, 1 H); 2.45-2.55 (m, 2 H); 1.85 (t, J=10.6 Hz, 2 H); 1.71-1.68 (m, 2 H); 1.40-1.34 (m, 2 H); 1.35 (d, J=6.80 Hz, 6 H)
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][O:4][N:3]=1.O>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][O:4][N:3]=1
Reactant: CCOC(=O)c1conc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nocc1C(=O)O
Yield: 93.9 %

Procedure:
Ethyl 3-methyl-4-isoxazolecarboxylate (1.3 g) is stirred at room temperature overnight in 5 mL of ethanol and 10 mL of 2.5 N sodium hydroxide. Dilution with water, cooling in ice, and acidification to pH 2 with 6 N hydrochloric acid precipitates an off-white solid which is collected by vacuum filtration, washed with ethanol/water, and dried under vacuum to give 1.0 g of 3-methyl-4-isoxazolecarboxylic acid.
Reaction SMILES: C([N:4]1[C:9](=[O:10])[C:8]([Br:11])=[CH:7][C:6]2[CH:12]=[N:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[C:5]1=2)C=C.C[N+]1([O-])CC[O:27]CC1.[C:31]([OH:35])(C)([CH3:33])[CH3:32]>O.S([O-])([O-])=O.[Na+].[Na+]>[Br:11][C:8]1[C:9](=[O:10])[N:4]([CH2:32][CH:31]([OH:35])[CH2:33][OH:27])[C:5]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:13]=[CH:12][C:6]=2[CH:7]=1
Reactant: CC(C)(C)O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCn1c(=O)c(Br)cc2cnn(-c3ccc(F)cc3F)c21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1c(Br)cc2cnn(-c3ccc(F)cc3F)c2n1CC(O)CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 7-allyl-5-bromo-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (265 mg, 0.724 mmol) in tert-BuOH (5 mL) and water (5 mL) at RT was treated with 4-methylmorpholine N-oxide (127 mg, 1.09 mmol) and potassium osmate dihydrate (10 mg, 0.027 mmol). The resulting mixture was allowed to stir for 16 h at RT, then diluted with an aqueous solution of sodium sulfite (10 mL) and extracted with EtOAc (3×25 mL). The organic extracts were dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO 12 g column (0-5% MeOH:DCM) affording the title compound as a white amorphous solid. MS (ESI, pos.ion) m/z: 399.0/401.0 (M+1).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OCC)(=O)C.O>C1COCC1>[Br:17][C:12]1[C:13]([CH3:15])=[CH:14][C:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:10][C:11]=1[F:16].[Br:17][C:14]1[C:13]([CH3:15])=[CH:12][C:11]([F:16])=[CH:10][C:9]=1[O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: Cc1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1Br
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(F)c1Br
Reaction time: 1 h
Yield: 184.9 %

Procedure:
To a solution of tert-butyl(3-fluoro-5-methylphenoxy)dimethylsilane (17.0 g, 70.8 mmol) in THF (300 mL) as added N-bromosuccinimide (18.9 g, 106 mmol) at room temperature, and the mixture was stirred for 1 h. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (98:2 hexane/ethyl acetate) to give a mixture (ca. 4:1) of (4-bromo-3-fluoro-5-methylphenoxy)(tert-butyl)dimethylsilane and (2-bromo-5-fluoro-3-methylphenoxy)(tert-butyl)dimethylsilane (20.9 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([O:24][CH3:25])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:34][CH:35]([CH3:39])[C:36](=[S:38])[NH2:37]>C(Cl)Cl.CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:38][C:36]([CH:35]([CH3:39])[CH3:34])=[N:37][C:9]=2[C:11]2[C:12]([O:24][CH3:25])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1OC
Reactant: CC(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of 2-propen-1-yl [3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamate (15.4 g, 42 mmol) in DCM (150 mL), NBS (7.6 g, 42 mmol) was added and the solution was allowed to stir at rt for 30 min. The reaction mixture was then concentrated in vacuo and the resulting oil was diluted with DMSO (150 mL) and 2-methylpropanethioamide (6.6 g 63.8 mmol) was added at once. The reaction was complete after stirring 1 h at rt. The reaction mixture was diluted with EtOAc and organic layer was washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound of Step F (12.1 g, 63.8% yield) which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([Cl:10])[CH:3]=1.[C-:11]#[N:12].[K+]>ClC(Cl)C.O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: O
Product: N#CCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 290.2 %

Procedure:
To a stirred solution of 4-bromo-1-bromomethyl-2-chlorobenzene (16, 62.5 g, 0.22 mol) in dichloroethane (522 mL) and water (480 mL) was added tetrabutylammonium chloride (5.05 g), followed by a solution of potassium cyanide (43.2 g, 75.8 mmol) in water (523 mL). and the solution was stirred for 4 h at room temperature. The layers were separated and the aqueous layer was extracted with dichloroethane (100 mL). The combined organic layers were washed with water (100 mL), dried over sodium sulfate filtered and evaporated. The crude product (52 g) was distilled under reduced pressure (1 mmHg), affording (4-bromo-2-chlorophenyl)-acetonitrile (45.5 g, 0.220 mol, 90%).
Reaction SMILES: Cl[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[NH2:13][C:14]1[C:29]([Cl:30])=[CH:28][C:17]([C:18]([O:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:19])=[C:16]([O:31][CH3:32])[CH:15]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:13][C:14]1[C:29]([Cl:30])=[CH:28][C:17]([C:18]([O:20][CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:4][CH2:3][CH2:2][O:5][C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:26][CH2:27]2)=[O:19])=[C:16]([O:31][CH3:32])[CH:15]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)OCC1CCNCC1
Reactant: CCC(Cl)Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)OCC1CCN(CCCOc2ccc(F)cc2)CC1
Temperature: 70 °C
Reaction time: 48 h
Yield: 25.8 %

Procedure:
A mixture of 1-chloro-(4-fluorophenoxy)propane (2.3 g), intermediate 11 (3 g) and N,N-diethylethanamine (2.8 ml) in DMF (50 ml) was stirred for 48 hours at 70° C. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN (0° C.). The precipitate was filtered off and dried (vacuum; 50° C.), yielding 1.17 g (26%) [1-[3-(4-fluorophenoxy)propyl]-4-piperidinyl]methyl 4-amino-5-chloro-2-methoxybenzoate (compound 1, mp. 140.0° C.).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[Cl:13][C:14]1[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=1.N>>[ClH:13].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:19]([C:17]3[S:18][C:14]([Cl:13])=[CH:15][CH:16]=3)=[O:20])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Cl)s1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-chlorothiophene-2-carboxylic acid (Aldrich) according to methods A and C; yield 62 mg, 0.19 mmol (59%): 1H NMR (300 MHz, methanol-d4) δ 2.05-2.26 (m, 5H), 2.43 (s, 2 H), 3.47 (d, J=13 Hz, 2H), 3.54 (s, 2H), 3.78 (d, J=13 Hz, 2H), 4.21 (t, J=3 Hz, 1H), 7.04 (d, J=4 Hz, 1H), 7.70 (d, J=4 Hz, 1H); MS (DCI/NH3) m/z 297, 299 (M+H)+; Anal. C14H17ClN2OS.HCl: C, H, N.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[CH:15][CH2:16][CH:17]([OH:27])[C:18]2[CH:19]=[C:20]([Si:23]([CH3:26])([CH3:25])[CH3:24])[O:21][CH:22]=2)[CH:13]=[O:14])=[CH:4][C:3]2[CH:28]=[CH:29][CH:30]=[CH:31][C:2]1=2>C1C=CC=CC=1>[S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]([OH:14])[O:27][CH:17]([C:18]3[CH:19]=[C:20]([Si:23]([CH3:26])([CH3:25])[CH3:24])[O:21][CH:22]=3)[CH2:16][CH:15]=2)=[CH:4][C:3]2[CH:28]=[CH:29][CH:30]=[CH:31][C:2]1=2
Reactant: C[Si](C)(C)c1cc(C(O)CC=C(C=O)CCCCCCc2cc3ccccc3s2)co1
Solvent: c1ccccc1
Product: C[Si](C)(C)c1cc(C2CC=C(CCCCCCc3cc4ccccc4s3)C(O)O2)co1

Procedure:
2-(6-(Benzo(b]thien-2-yl)-hexyl]-5-hydroxy-5-(2-trimethylsilyl-4-furyl)-2-pentenal (0.142 g., 0.31 mmol) was dissolved in 30 ml anhydrous benzene, placed in a quartz tube, and subjected to four freeze, pump, thaw cycles. The tube was flushed with argon and irradiated at 254 nm for 2.5 hours. The solution was concentrated to give an orange gum. This material was purified by flash chromatography (silica, 5 to 30% ethyl acetate/hexane. First eluted was the desired hydroxy acetal as a yellow gum. Second eluted was starting aldehyde as a clear gum.
Reaction SMILES: [OH-].[K+].[CH3:3][C@@H:4]1[CH2:8][CH2:7][C:6](=O)[CH:5]1[C:10]([O:12]CC)=O.[NH2:15][C:16]([NH2:18])=[S:17]>O.C(O)C>[SH:17][C:16]1[N:15]=[C:10]([OH:12])[C:5]2[C@H:4]([CH3:3])[CH2:8][CH2:7][C:6]=2[N:18]=1
Reactant: CCOC(=O)C1C(=O)CC[C@H]1C
Reactant: NC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@@H]1CCc2nc(S)nc(O)c21
Yield: 56 %

Procedure:
KOH (8.3 g, 147.9 mmol) in water (60 mL) was added to a solution of a mixture of (2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (20 g, 117.5 mmol) and thiourea (9.2 g, 120.9 mmol) in ethanol (100 mL). The mixture was refluxed for 10 hours. After cooling, the solvent was removed and the residue was neutralized with concentrated HCl (12 mL) at 0° C. and then extracted with DCM (3×150 mL). The solvent was removed, and the residue was purified by silica gel chromatography, eluting with hexane/ethyl acetate (2:1) to give (R)-2-mercapto-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12 g, 56%). MS (APCI+) [M+H]+ 183.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH:15][CH2:16][C:17]([NH2:26])([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH3:18])[CH2:6]1)[CH2:12]2)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[N:15]3[CH2:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)([CH3:18])[NH:26][C:28]3=[O:30])[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C12CC3CC(C1)C(NCC(C)(N)c1cccc(Cl)c1)C(C3)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C12CC3CC(C1)C(N1CC(C)(c4cccc(Cl)c4)NC1=O)C(C3)C2
Reaction time: 4 h
Yield: 118.8 %

Procedure:
A solution of 4-[2-amino-2-(3-chloro-phenyl)-propylamino]-adamantane-1-carboxylic acid methyl ester (7.9 g) in 40 mL DCM was cooled to −20° C. and triphosgene (3.1 g) (separately dissolved in 10 mL DCM) was added to it drop wise followed by drop wise addition of triethylamine (6.57 mL). The reaction mixture was slowly brought to RT and left at stirring for 4 h. Reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and the DCM layer was separated. The aqueous layer was again extracted with DCM (2×). The combined DCM layers were dried over Na2SO4 and concentrated to afford the crude product, which was purified by column chromatography to give the desired 4-[4-(3-chloro-phenyl)-4-methyl-2-oxo-imidazolidin-1-yl] adamantane-1-carboxylic acid methyl ester (5.0 g) as a mixture of E/Z isomers as a white solid. MS (ES+): 403.4 (MH+).