Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[Br:17]Br.O>ClCCl.[Fe]>[Br:17][C:7]1[C:2]([OH:1])=[C:3]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=[C:5]([CH3:8])[CH:6]=1
Reactant: BrBr
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: [Fe]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Br)c(O)c(C(=O)c2ccccc2)c1
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
To a solution of 116 g (0.55 mol) of 32 in 200 mL of dry dichloromethane 1.5 g of iron turnings was added, and then a solution of 41.4 mL (136 g, 0.83 mol) of bromine in 500 mL of dichloromethane was added dropwise with vigorous stirring for 20 min. This mixture was refluxed for 30 min, and then 1200 mL of water was added. The organic layer was separated, and the aqueous layer was extracted with 2×300 mL of dichloromethane. The combined organic extract was washed by saturated aqueous Na2SO3, dried over K2CO3, and then evaporated to dryness. Drying the residue in vacuum gave 138 g (86%) of 33 (bp 165-172° C./1 mm).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[C:16]([OH:18])=O)[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:35])[CH2:3][CH2:2]1.Cl.[CH3:37][N:38](C)CCCN=C=NCC.CN>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:19]4[CH:20]=[CH:21][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:23][CH:24]=4)[C:16]([NH:38][CH3:37])=[O:18])[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:35])[CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A solution of 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(4-(quinolin-7-yl)phenyl)acetic acid (0.191 mmol) in dichloromethane (2 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.286 mmol) and 4-(dimethylamino)pyridine (0.763 mmol) at room temperature. After stirring for 10 minutes, this mixture was treated with methanamine (2M in THF) (0.400 mmol). The reaction vessel was sealed and the reaction was allowed to stir at room temperature for 16 hours. At this point an additional portion of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.15 mmol) and methanamine (2M in THF) (0.400 mmol) was added and the solution was allowed to stir at room temperature for 3 hours. The reaction was concentrated under a nitrogen stream. Purification of the residue by reverse phase HPLC (5-35% acetonitrile with 0.1% TFA/water with 0.1% TFA) and then by silica gel chromatography (0-9% methanol/dichloromethane) followed by lyophilization from water with 10% acetonitrile (1 mL) afforded the title compound (26%) as a white solid. MS(ES)+ m/e 485.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:6]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1.[H-].[Na+].[CH2:30](I)[CH3:31].O>CN(C)C=O>[CH2:30]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:6]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[C:7]1[C:14]([O:16][CH3:17])=[O:15])[CH3:31]
Reactant: COC(=O)c1[nH]c2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of methyl 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (7.5 g) in N,N-dimethylformamide (100 ml) was added oily sodium hydride (60%, 1.6 g) and the mixture was stirred for 30 minutes at room temperature. After dropwise addition of ethyl iodide (4.8 ml), the reaction mixture was further stirred for 2 hours at room temperature, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethyl ether to give methyl 1-ethyl-5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (6.38 g, 77%) as pale red prisms.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13].O>C1COCC1.CO>[CH3:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[OH:13]
Reactant: Cc1cccc2c1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c1CCC2O
Yield: 99 %

Procedure:
NaBH4 is added, in portions, at 0° C., to the solution of 4-methyl-1-indanone in THF/CH3OH. After 3 hours the mixture is poured into water and extracted with ether. After washing the organic extracts to neutrality and anhydrifying on Na2SO4, the solvent is evaporated under vacuum. 22.0 g of 4-methyl-1-indanol are obtained (yield=99%).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:23]=[CH:22][C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH3:21])=O)=[CH:9][CH:8]=1.Cl>O1CCCC1>[Cl:20][C:17]1[CH:16]=[C:15]2[C:14](=[CH:19][CH:18]=1)[NH:13][C:11]([C:10]1[CH:22]=[CH:23][C:7]([Cl:6])=[CH:8][CH:9]=1)=[CH:21]2
Reactant: Cc1cc(Cl)ccc1NC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccc(-c2cc3cc(Cl)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
n-Butyllithium (1.6M in hexanes, 127 mL, 203 mmol) was added dropwise to a stirred, cooled (−10° C.) solution of 4-chloro-N-(4-chloro-2-methylphenyl)benzamide (Description 27, 27.1 g, 97 mmol) in tetrahydrofuran (600 mL). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0° C. and further n-butyllithium (1.6M in hexanes, 30 mL, 483 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h., then hydrochloric acid (2.5M, 200 mL) was added. The mixture was stirred at room temperature overnight, then extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (85:15), to give the title compound (3.6 g, 14%). 1H NMR (360 MHz, CDCl3) δ 8.30 (1H, br s), 7.57 (3H, m), 7.42 (2H, d, J 9.1 Hz), 7.30 (1H, d, J 8.6 Hz), 7.15 (1H, dd, J 8.6, 2.0 Hz) and 6.74 (1H, s).
Reaction SMILES: [Si]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24](=[N:26][C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])[CH3:25])[CH2:20]2)=[O:17])[N:13]([C:40]([C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=2)=[O:45])=[C:41]([CH3:43])[CH3:42])[C:12]1=[O:57])[CH3:10])(C(C)(C)C)(C)C.B(F)(F)F.CCOCC>C(#N)C.C(OCC)(=O)C>[OH:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24](=[N:26][C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=3)=[O:28])[CH3:25])[CH2:20]2)=[O:17])[N:13]([C:40]([C:44]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][C:51]([N+:54]([O-:56])=[O:55])=[CH:52][CH:53]=2)=[O:45])=[C:41]([CH3:42])[CH3:43])[C:12]1=[O:57])[CH3:10]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(C)C)C1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(C)C)C1
Reaction time: 2.5 h
Yield: 104.7 %

Procedure:
511 mg (0.62 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-([(S)-1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl)-1 -[2-methyl-1-(p-nitrobenzyloxycarbonyl)prop-1-enyl]-2-azetidinone were dissolved in 20 ml of acetonitrile. To this solution were added 176 mg (1.24 mmole) of boron trifluoride etherate, with stirring and ice-cooling. The reaction mixture was then left to stand at room temperature for 2.5 hours, after which it was diluted with ethyl acetate, washed with an aqueous solution of sodium bicarbonate and dried. The solvent was distilled off, to afford 462 mg of the title product.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1)[C:3]([NH:5][NH:6][C:7](=[O:31])[C:8]1[C:13]([O:14]CC2C=CC=CC=2)=[CH:12][C:11]([O:22]CC2C=CC=CC=2)=[CH:10][C:9]=1[Cl:30])=[O:4].Cl>C1COCC1>[OH:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1)[C:3]([NH:5][NH:6][C:7](=[O:31])[C:8]1[C:13]([OH:14])=[CH:12][C:11]([OH:22])=[CH:10][C:9]=1[Cl:30])=[O:4]
Reactant: O=C(NNC(=O)C(O)c1cccc(O)c1)c1c(Cl)cc(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NNC(=O)C(O)c1cccc(O)c1)c1c(O)cc(O)cc1Cl

Procedure:
720 mg of N′-[2-hydroxy-2-(3-hydroxyphenyl)acetyl]-2-chloro-4,6-dibenzyloxybenzohydrazide in 20 ml of THF+0.2 ml of 32% HCl are hydrogenated with the calculated amount of H2 using 360 mg of PdoC. The hydrogenation solution is evaporated and chromatographed on silica gel. The uniform fractions are combined, evaporated and recrystallised from EtOAc. Yield 310 mg (65%) of “A15”, m.p. 230-231°.
Reaction SMILES: [N:1](=[C:3]1[S:8][CH2:7][S:6][CH2:5][S:4]1)[OH:2].[CH3:9][N:10]=[C:11]=[O:12]>CC(C)=O.C(N(CC)CC)C>[CH3:9][NH:10][C:11]([CH:7]1[S:8][C:3](=[N:1][OH:2])[S:4][CH2:5][S:6]1)=[O:12]
Reactant: ON=C1SCSCS1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)C1SCSC(=NO)S1
Reaction time: 72 h

Procedure:
A quantity of 3.3 g of 2-oximino-1,3,5-trithiane and 1.29 ml of methyl isocyanate were dissolved in 50 ml of acetone containing 0.05 ml of triethylamine in a glass pressure vessel. The reaction mixture was allowed to stand for 72 hours at ambient temperature. The solvent was then evaporated and the residue taken up in 200 ml of ethyl acetate. The solution was washed with water, dried over magnesium sulfate and the solvent evaporated off. Recrystallization from isopropyl ether/acetone yielded 2.47 g of 2-methylcarbamoyloximino-1,3,5-trithiane, mp 129°-130°. The compound is identical in spectral properties to that obtained in Example II.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([C:13]1[N:17]2[N:18]=[C:19]([C:22]3[N:26]4[CH2:27][CH2:28][CH2:29][C:25]4=[N:24][C:23]=3[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH:20]=[CH:21][C:16]2=[N:15][N:14]=1)([CH3:12])[CH3:11])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C:23]1[N:24]=[C:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:22]=1[C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([C:10]([CH3:12])([CH3:11])[CH2:9][OH:8])=[N:14][N:15]=2)[N:18]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(CO)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Yield: 15.5 %

Procedure:
The 3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine (0.606 g, 1.16 mmol, Preparation #E.1.1.1) was dissolved in THF (15 mL) and reacted at about ambient temperature with TBAF (1.0 M in THF, 1.39 mL, 1.39 mmol) for about 4 h. The crude reaction mixture was partitioned between water and DCM. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude material was purified by chromatography on silica gel (DCM/MeOH gradient from 100:0-85:15) and triturated with a mixture of heptane/Et2O (90:10) to give the title compound as a yellow solid (0.074 g, 16%): LC/MS (Table 1, Method g) Rt=1.64 min.; MS m/z: 411.98 (M+H)+.
Reaction SMILES: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2(O)[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:31]([OH:51])[CH:30]=1>>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:31]([OH:51])[CH:30]=1
Reactant: CCCCCN1C(=O)C(O)(c2ccc(Br)cc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCCCCN1C(=O)C(c2ccc(Br)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (91%) as a white powder: 1H NMR (300 MHz, CDCl3) δ 7.40 (t, 1H), 7.31 (d, 1H) 7.24-7.23 (m, 2H), 7.01-6.91 (m, 2H), 6.74 (d, 1H), 5.05 (br, 1H), 3.80-3.65 (m, 2H), 1.75-1.63 (m, 2H), 1.38-1.29 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 374.4 (M+1), 376.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:25]=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28].C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:25][NH:31][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccc(OCc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NC[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 18.3 %

Procedure:
A solution consisting of 2.86 g (8 mmol) N-tert-butoxycarbonyl-O-benzyl-L-tyrosinal (Example 4, Step A) and 0.846 mL (8 mmol) tert-butyl amine (Aldrich, Milwaukee, Wis.) in 36 mL methanol containing 1% acetic acid was stirred at 25° C. for 20 minutes, at which time a solution of 1.06 g (16 mmol) sodium cyanotrihydridoborate (Aldrich, Milwaukee, Wis.) in 12 mL methanol was added and the resulting mixture stirred for 48 hours. The reaction was quenched by the addition of 3 M HCl in 3 mL increments until the vigorous bubbling subsided. The mixture was neutralized with saturated NaHCO3 solution then extracted with three 100 mL portions of ethyl acetate. The combined extracts were washed with 100 mL brine, dried over anhydrous sodium sulphate and evaporated at reduced pressure to give a pale amber oil which was chromatographed on a silica gel column using 1% to 2% methanol in ethyl acetate as eluant to give 604 mg (18%) of the title compound as waxy white crystals; mp 77-79° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: ClCCCBr
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Product: COC(=O)c1cc(OCCCCl)ccc1[N+](=O)[O-]
Yield: 94 %

Procedure:
Methyl 5-hydroxy-2-nitrobenzoate (4.37 g, 22.17 mmol, prepared as previously described), and 1-bromo-3-chloropropane (6.58 mL, 66.5 mmol) were reacted using the procedure described in Example 40A Step 3 to give methyl 5-(3-chloropropoxy)-2-nitrobenzoate (5.70 g, 20.8 mmol, 94%). 1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, 1H), 7.33 (d, 1H), 7.30 (dd, 1H), 4.27 (dt, 2H), 3.86 (s, 3H), 3.68 (t, 2H), 2.21 (t, 2H); LC-MS (ESI) m/z 274 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[C:13]([O-:16])(=[O:15])[CH3:14].[K+].C(O)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:13]([O:16][CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: COC(=CC(=O)C(F)(F)F)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=CC(=O)C(F)(F)F)COC(C)=O

Procedure:
24.8 g (0.1 mol) of 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one, 20 g of potassium acetate, 5 g of tetrabutylammonium bromide and 8 g of acetic acid were stirred in 300 ml of acetonitrile at 40° C. for 20 h. The precipitate was filtered off and the solvent was removed completely under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23](SC)=[N:24][CH:25]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:23]2[NH:22][C:21](=[O:28])[C:20]([CH2:19][C:18]3[CH:29]=[CH:30][CH:31]=[C:16]([O:15][CH3:14])[CH:17]=3)=[CH:25][N:24]=2)=[N:6][CH:7]=1
Reactant: COc1cccc(Cc2cnc(SC)[nH]c2=O)c1
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: c1ccncc1
Product: COc1cccc(Cc2cnc(NCCCCc3ncc(Br)cc3C)[nH]c2=O)c1
Yield: 67.5 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.58 g) and 5-(3-methoxybenzyl)-2-methylthio-4-pyrimidone (0.51 g) were refluxed in pyridine (3 ml) for 3 hours. The pyridine was removed in vacuo. The residue was recrystallised from ethanol/water giving 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(3-methoxybenzyl)-4-pyrimidone (0.60 g). Softens 65° C., melts 73° C.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=2[C:9]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:23][CH:22]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=2[C:9]=1[CH:19]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:26]=1)[OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccccc3)sc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccccc3)sc2c1
Reaction time: 0.33 h
Yield: 84 %

Procedure:
Dissolve crude (2-benzyl-6-methoxy-benzo[b]thiophen-3-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone in THF (10 mL) at r.t. Add LAH solution (3 mL of 1M/THF) dropwise while stirring. Continue stirring for 20 min. and quench with aq. NaHCO3. Dilute the reaction mixture with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0–5% (2M NH3 in MeOH)/CH2Cl2) to yield (2-benzyl-6-methoxy-benzo[b]thiophen-3-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanol (755 mg, 84%, 2 steps).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.Br[CH2:13][CH2:14][O:15][CH3:16].O>CN(C=O)C>[CH3:16][O:15][CH2:14][CH2:13][N:11]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[S:2][CH3:1]
Reactant: COCCBr
Reactant: CSc1nc2cccnc2[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(SC)nc2cccnc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A mixture of 2-(methylthio)-3H-imidazo[4,5-b]pyridine (400 mg) and 1-bromo-2-methoxyethane (370 mg) in DMF (7 mL) was stirred at 80° C. for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (200 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([NH2:21])=O.[OH-].[Na+]>O>[NH2:21][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: NC=O
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 140 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A mixture of 4-chloro-1-isobutyl-1H-imidazo[4,5-c]-quinoline (50.0 g, 0.192 mol) and formamide (125 ml, 3.136 mole, 16.3 equiv.) was heated at about 140° C. under nitrogen atmosphere for 26 hours. Then, the reaction mixture was cooled to 95° C. and water (10 ml) was added. The reaction mixture was heated at this temperature for 2 hours. Water (250 ml) and 47% aqueous sodium hydroxide solution were then added to produce a pH of about 9 and the mixture was stirred at ambient temperature for 2 hours. A solid was collected by filtration, washed with water (3×50 ml) and methanol (3×50 ml) and dried at 50° C. under reduced pressure overnight to give crude 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (Imiquimod) (39.0 g). The crude compound (39.0 g) was slurried in a mixture of methanol (500 ml) and 47% aqueous sodium hydroxide solution (about 33.0 ml) under reflux for 6 hours. The mixture was cooled to ambient temperature and a colorless solid was collected by filtration, washed with methanol (3×20 ml), water (3×20 ml) and methanol (3×20 ml) and dried at 50° C. under reduced pressure overnight to yield 22.0 g of Imiquimod in 47.6% yield, having a purity of 98.2% (by HPLC). The product was crystallized from N,N-dimethylformamide to afford colorless Imiquimod having a purity of 99.9% (by HPLC).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:10]1([C:14]([NH:16][NH2:17])=[O:15])[CH2:13][CH2:12][CH2:11]1>C(O)C>[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:17][NH:16][C:14]([CH:10]2[CH2:13][CH2:12][CH2:11]2)=[O:15])[CH3:2])=[CH:5][CH:6]=1
Reactant: NNC(=O)C1CCC1
Reactant: CC(=O)c1ccncc1
Solvent: CCO
Product: CC(=NNC(=O)C1CCC1)c1ccncc1
Yield: 26.9 %

Procedure:
A mixture of 6.06 gm (0.05 mole) of 4-acetylpyridine, 5.7 gm (0.05 mole) of cyclobutanecarboxylic acid hydrazide, and 100 ml of absolute ethanol is refluxed 5 hours. The reaction mixture is evaporated in vacuo to give a solid. The product is crystallized from ethanol/ethylacetate/diethylether to give 2.92 gm (27%) of the title compound; mp 138.6°.
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH2:6]1)([CH3:3])[CH3:2].Br[C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]=1[CH3:31].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8]([C:21]2[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]=2[CH3:31])=[CH:7][CH2:6]1)([CH3:2])[CH3:3]
Reactant: CC(C)OC1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOC(=O)c1noc(Br)c1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1noc(C2=CCC(OC(C)C)CC2)c1C

Procedure:
To a 2-5 mL microwave vial containing a solution of [2-(4-isopropoxycyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane] (375 mg, 1.410 mmol) in acetonitrile (2 mL), ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (330 mg, 1.410 mmol) was added followed by K2CO3 (585 mg, 4.23 mmol), PdCl2(dppf).CH2Cl2 adduct (11.51 mg, 0.014 mmol) and water (2 mL). The vial was flushed with nitrogen and treated in the microwave (Biotage Smith Initiator) at 80° C. for 90 minutes. The reaction mixture was partitioned between water (30 mL) and EtOAc (30 mL). The organic phase was washed with brine (30 mL), dried over MgSO4, filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-60% EtOAc in iso-hexane afforded the title compound;