Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].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][CH2:52][CH2:53][CH2:54][N:55]4[CH2:59][CH2:58][CH2:57][S:56]4(=[O:61])=[O:60])[C:49]([CH2:62][O:63][CH2:64][CH3:65])=[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.C(#N)C>[NH2:47][C:43]1[C:42]2[N:48]=[C:49]([CH2:62][O:63][CH2:64][CH3:65])[N:50]([CH2:51][CH2:52][CH2:53][CH2:54][N:55]3[CH2:59][CH2:58][CH2:57][S:56]3(=[O:61])=[O:60])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37](/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])=[CH:46][C:45]=2[N:44]=1
Reactant: C=CC(=O)OC
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN1CCCS1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(/C=C/C(=O)OC)ccc3c2n1CCCCN1CCCS1(=O)=O
Temperature: 90 °C

Procedure:
A 50-mL thick walled glass vessel was charged with palladium (II) acetate (67 mg, 0.3 mmol), acetonitrile (2 mL), methyl acrylate (0.26 g, 3.0 mmol), triethylamine (0.9 g, 9.0 mmol), tri-o-tolylphosphine (0.18 g, 0.6 mmol) and 7-bromo-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (U.S. Patent Application Publication No. US 2004/0147543 Example 152-156, 1.5 g, 3.0 mmol). An additional 13 mL of acetonitrile was added. The reaction mixture was purged with nitrogen then heated to 90° C. The turbid orange mixture was maintained at 90° C. overnight. Anhydrous DMF (30 mL) was added to dissolve the 7-bromoquinoline starting material. The reaction was then heated at 120° C. overnight. The reaction mixture was filtered to remove the catalyst then concentrated to dryness. The desired product was isolated by column chromatography on silica gel (eluting with a gradient of 2%-8% methanol in dichloromethane). The resulting peach solid was taken up in saturated potassium carbonate solution and dichloromethane and stirred overnight at ambient temperature. The organic layer was separated and concentrated to dryness. The residue was recrystallized from acetonitrile to yield 0.65 g of Methyl(2E)-3-[4-amino-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as a pale yellow solid, mp 162-163° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:20].O.C(C(O)=O)(F)(F)F>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:20])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCCl
Yield: 32.8 %

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodo]benzene (15.6 g, 36.2 mmol), H2O (18 ml), CF3CO2H (2.8 ml) and CH3CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99°-101° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1.[Br:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1.C(O[Na])(C)(C)C>CS(C)=O>[Br:17][C:18]1[C:19]([O:16][CH:13]2[CH2:14][CH2:15][CH:10]([C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH2:11][CH2:12]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1ncccc1Br
Reactant: OC1CCC(c2nc3ccccc3[nH]2)CC1
Agent: CC(C)(C)O[Na]
Solvent: CS(C)=O
Product: Brc1cccnc1OC1CCC(c2nc3ccccc3[nH]2)CC1
Temperature: 60 °C
Yield: 24.1 %

Procedure:
The mixture of 4-(1H-benzoimidazol-2-yl)-cyclohexanol (0.36 g, 1.67 mmol), 3-bromo-2-chloro-pyridine (0.64 g, 3.34 mmol), t-BuONa (0.37 g, 3.34 mmol) and DMSO (5 mL) was heated at 60° C. for 2 days under N2 atmosphere. Then the mixture was concentrated under vacuum and the obtained residue was purified by silica gel chromatograph (DCM:MeOH=10:1) to give 2-[4-(3-bromo-pyridin-2-yloxy)-cyclohexyl]-1H-benzoimidazole (0.15 g, 0.403 mmol, 36% yield) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([F:37])[CH2:13][CH2:14][C:15]1([C:32]([O:34]CC)=[O:33])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[CH2:17][CH2:16]1)=[CH:9][C:8]([O:38][CH3:39])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([F:37])[CH2:13][CH2:14][C:15]1([C:32]([OH:34])=[O:33])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[CH2:19][CH2:20]1)=[CH:9][C:8]([O:38][CH3:39])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCC(F)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCOc2cc(F)ccc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ncc(Cl)c(C(F)CCC3(C(=O)O)CCN(CCOc4cc(F)ccc4F)CC3)c2c1
Temperature: 70 °C
Yield: 28.1 %

Procedure:
A mixture of 0.15 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 1 cm3 of aqueous 5N sodium hydroxide solution was maintained at a temperature in the region of 70° C. for 4 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue was chromatographed under an atmospheric pressure of 60 kPa, on a Bond Elut of 60 cm3 of silica gel (particle size 70-200μ; mass 25 g), eluting with 60 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and then with a dichloromethane/methanol/aqueous ammonia mixture (40/5/2 by volume). The fractions containing the expected product were combined and then concentrated to dryness according to the same conditions as above. 0.04 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[N+:22]([CH2:25][CH3:26])([O-:24])=[O:23]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:10])[CH:25]([N+:22]([O-:24])=[O:23])[CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=CCc1cccc(Br)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C(O)Cc1cccc(Br)c1)[N+](=O)[O-]
Reaction time: 3 h
Yield: 43.8 %

Procedure:
To a solution of 2-(3-bromophenyl)acetaldehyde (5.0 g, 0.025 mol) and DBU (7.6 mL, 0.05 mol) in THF (300 mL), Nitroethane (1.0 g, 0.03 mol) was added at 0° C. over 10 min. The reaction mixture was stirred for 3 h, quenched by the addition of H2O (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with H2O (2×30 mL) and brine (1×20 mL), dried over Na2SO4, filtered and concentrated to afford 1-(3-bromophenyl)-3-nitrobutan-2-ol (3.0 g, 44%) as a yellow oil. MS (ES+) C10H12BrNO3 requires: 273, 275 found: 274, 276 [M+2+H]+(1:1).
Reaction SMILES: CN(C)[CH:3]=[O:4].[H-].[Na+].[OH:8][C:9]1[C:26]([OH:27])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([OH:29])=[C:21]([OH:28])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([OH:31])=[C:15]([OH:30])[CH:16]=3)[C:11]=2[CH:10]=1.C1(C)C=CC(S(OO[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[O:8]([C:9]1[C:26]([O:27][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:29][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])=[C:21]([O:28][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([O:31][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:4][CH3:3])=[C:15]([O:30][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])[CH:16]=3)[C:11]=2[CH:10]=1)[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49]
Reactant: Oc1cc2c3cc(O)c(O)cc3c3cc(O)c(O)cc3c2cc1O
Reactant: CN(C)C=O
Reactant: COCCOCCOOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCCOCCOc1cc2c3cc(OCCOCCOC)c(OCCOCCOC)cc3c3cc(OCCOCCOC)c(OCCOCCOC)cc3c2cc1OCCOCCOC
Reaction time: 1 h
Yield: 5 %

Procedure:
In a reaction vessel, 15 ml of dry N,N-dimethylformamide (DMF) and 0.77 g (19.3 mM) of NaH (60 W in mineral oil) were placed. Then, 0.92 g (2.84 mM) of 2,3,6,7,10,11-hexahydroxytriphenylene was added thereto on a water bath, and after 1 hour of stirring, a mixture liquid of 6.4 g (23.3 mM of 1,4,7-trioxaoctyl p-toluenesulfonate and 5 ml of dry DMF was added dropwise thereto, followed by 5 hours of stirring at 80° C. After the reaction, water was added to the reaction mixture, followed by extraction two times with toluene. The extract was washed with water and dried with anhydrous sodium sulfate, followed by distilling-off the solvent and purification three times by silica gel column chromatography (eluent: chloroform to obtain 0.14 g (0.15 mM) of 2,3,6,7,10,11-hexa(1,4,7-trioxaoctyl)triphenylene (Yield: 5%), which showed a melting point of 54 ° C.
Reaction SMILES: [O:1]=[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[C:3]1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:25][C:26]([CH3:31])([CH3:30])[C:27]([O:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:3]2[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13]1)=[O:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=c1cccccc1N1CCN(CCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCCN1CCN(c2cccccc2=O)CC1
Reaction time: 72 h

Procedure:
To a solution of 4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-ethanol (7.04 g, described in Example 7) in methylene chloride (100 ml), triethylamine (4.3 g) was added followed by the dropwise addition of 2,2-dimethylpropanoyl chloride. The resulting solution was allowed to stay at room temperature for 3 days, then washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed twice on 250 g of silica gel with ethyl acetate to yield 3.5 g of the title compound. The title compound (3.0 g) was dissolved in acetone (15 ml) and a solution of maleic acid (1.16 g) in acetone (15 ml) was added. Diethyl ether (100 ml) was added to give the (Z)-2-butenedioate salt (2.5 g) of the title compound; mp 101°-102° C.; ir(mull) 2350, 1723, 1700 and 1545 cm-1 ; uv max(MeOH) 343 (ε=8040) and 251 nm(ε=12645); nmr(DMSO-d6 ) δ1.2 (m, 9H), 3.3 (m, 10H), 4.3 (m, 2H), 6.1 (s, 2H) and 6.95 (m, 5H); and Anal. Calcd for C18H26N2O3.C4H4O4 : C, 60.82% H, 6.96% N, 6.45% and Found: C, 60.74% H, 7.01% N, 6.16%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>>[CH:19]1([CH2:18][O:17][C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][C:12]([C:13]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[OH:29])=[O:15])=[CH:11][N:10]=2)[CH2:21][CH2:20]1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-fluoro-phenyl)-6-cyclopropylmethoxy-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials, MS (ISP) 385.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O-:4])=[O:3].[Na+].[Cl:6][C:7]1[N:12]=[CH:11][C:10]2C(I)=[N:14][N:15]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]=2[CH:8]=1.[CH3:36]O>C(Cl)Cl>[Cl:6][C:7]1[N:12]=[CH:11][C:10]2[C:1]([C:2]([O:4][CH3:36])=[O:3])=[N:14][N:15]([C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]=2[CH:8]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 65 °C
Reaction time: 72 h

Procedure:
A suspension of NaOAc (1.415 g, 17.25 mmol), Pd(dppf)C12 (0.841 g, 1.150 mmol) and 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (6 g, 11.50 mmol) in MeOH (30 ml) was stirred under CO (120 psi) at 65° C. for 3 days. After reaction, the reaction mixture was diluted with DCM and dry loaded on silica column and purified by column chromatography on silica gel 120 g, eluting with 1:3 EA in Hexane to give the desired product as an off white solid 4.74 g (91% yield). MS ESI calc'd. for C27H20ClN3O2 [M+1]+ 454, found 454.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([O:16]C)[CH:3]=1.CN1CCCC1=O.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1
Reactant: COc1cc(Cl)c2c(c1)C(=O)c1ccccc1-2
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2c(Cl)cc(O)cc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Under an argon atmosphere, to 4-chloro-2-methoxy-9H-fluoren-9-one (92.0 g) were added N-methylpyrrolidone (120 ml) and pyridine hydrochloride (144 g). The reaction mixture was stirred at an oil bath temperature of 200° C. for 3 hr with removing water by a Dean-Stark apparatus. The reaction mixture was cooled to 90° C., water (600 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hr. The precipitated solid was collected by filtration, and washed with water (400 ml). The obtained solid was air-dried for 3 days, a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate 1:1, 300 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solid was collected by filtration, and washed with a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate=1:1, 500 ml). The obtained solid was dried under reduced pressure at 50° C. for 3 hr to give the title compound (48.6 g).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH3:22])[CH3:21])[CH2:16]2)=[CH:11][CH:10]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:23][CH2:24][C:25]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C@@H:17]([N:20]([CH3:22])[CH3:21])[CH2:16]2)=[CH:11][CH:10]=1)=[O:26]
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)CCl)cc2)C1
Reaction time: 3 h

Procedure:
Triethylamine (2.03 g) was added to a solution of (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine (3.15 g) in dichloromethane (120 ml), and then chloroacetyl chloride (2.26 g) was added dropwise. After 3 hours, the mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 281.79 (C14H20CIN3O); MS (ESI): 282 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].CCN(CC)CC.[CH:15]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:17][CH2:16]1>O1CCOCC1.O>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH:15]2[CH2:16][CH2:17]2)=[CH:25][CH:24]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)CNS(=O)(=O)c1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7.125 g (56.75 mmol) of glycine methylester hydrochloride in 60 ml of dioxane and 24 ml of H2O, 15 ml (107.8 mmol) of Et3N and then a solution of 10 g (40.53 mmol) of 4-cyclopropylmethoxy-benzenesulfonyl chloride in 10 ml of dioxane are added dropwise at 0-5° C. After stirring for 3 h at r.t., the reaction is quenched with ice water and the mixture is extracted with AcOEt. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound as a colorless solid; 1H-NMR (400 MHz, CDCl3): 0.3-0.40 (m, 2H), 0.65-0.72 (m, 2H), 1.20-1.35 (m, 1H), 3.65 (m, 3H), 3.77 (d, 2H, J=5.04 Hz), 3.86 (d, 2H, J=7.08 Hz), 4.98 (brs, 1H), 6.96 (d, 2H, J=8.52 Hz), 7.77 (d, 2H, J=8.52 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5](Br)[CH2:6][CH2:7][CH3:8])[CH3:2].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([S:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: COc1ccc(S)cc1
Reactant: CCCC(Br)C(=O)OCC
Product: CCCC(Sc1ccc(OC)cc1)C(=O)OCC

Procedure:
2-(4-Methoxy-phenylsulfanyl)-pentanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl2-bromovalerate (8.23 g, 39.3 mmol) and 4-methoxythiophenol (5 g, 35.7 mmol), 10.46 g (100%); clear oil; MS: 269 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:23]=1C=O.C(N)C1C=CC=CC=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][S:8](/[CH:11]=[CH:12]/[C:23]2[C:26]([O:32][CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])(=[O:10])=[O:9])=[CH:5][C:4]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Yield: 28 %

Procedure:
To a solution of 4-methoxy-3-nitrobenzyl sulfonylacetic acid (4.5 g, 15.5 mmol) in 30 mL of glacial acetic acid was added 2,4,6-trimethoxybenzaldehyde (3.05 g, 15.5 mmol) and a catalytic amount of benzylamine (0.6 mL). The resulting mixture was heated at reflux temperature for 6 h. The reaction mixture was then concentrated under reduced pressure to yield a gummy material. The gum was triturated with 2-propanol to yield a solid product. The solid product was recrystallized from a mixture of acetic acid and 2-propanol to provide the 2-((E)-2-(4-methoxy-3-nitrobenzylsulfonyl)vinyl)-1,3,5-trimethoxybenzene product in 28% yield. m.p. 186-187° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C)cc3)sc2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc3c(s2)CCCC(C(=O)O)=C3)cc1
Reaction time: 120 h
Yield: 84.9 %

Procedure:
To a solution of methyl 2—(4-methylphenyl)-7,8-dihydro-6H-cyclohepta[b]thiophene-5-carboxylate (803 mg) in ethanol-tetrahydrofuran (5-10 ml) was added 2N sodium hydroxide (2 ml) at room temperature, and the mixture was stirred for 5 days and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (10 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to precipitate crystals, which were collected by filtration and washed with diisopropylether to give 2—(4-methylphenyl)-7,8-dihydro-6H-cyclohepta[b]thiophene-5-carboxylic acid (650 mg) as pale yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)=[C:16]([CH:20]=1)[C:17]([O:19][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:18]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(COC(=O)c2cc(Br)ccc2OCc2ccc(C#N)cc2)cc1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
4-(Bromomethyl)benzonitrile (318 mg, 1.622 mmol) was added in a single charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (160 mg, 0.74 mmol) and potassium carbonate (204 mg, 1.48 mmol) in acetone (40 ml) at 20° C. The reaction mixture was stirred at 55° C. for 18 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (3×30 ml) and evaporated in vacuo to yield the title compound as an off-white solid. 300 mg.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[C:10]([CH3:12])[CH:9]=[N:8]1.[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25](I)=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14].O>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH3:6][N:7]1[C:11]([C:25]2[N:20]3[N:21]=[C:22]([CH3:24])[CH:23]=[C:18]([CH:15]([CH2:13][CH3:14])[CH2:16][CH3:17])[C:19]3=[N:27][C:26]=2[CH3:28])=[C:10]([CH3:12])[CH:9]=[N:8]1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1cnn(C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)cnn3C)c(C)nc12
Temperature: -72 °C
Reaction time: 0.08 h
Yield: 0.7 %

Procedure:
n-BuLi (1.3 ml, 2.09 mmol) is stirred in THF (4 ml), under N2, and cooled to −72° C. 1,4-dimethyl-1H-pyrazole (170 mg, 2.04 mmol, in THF, 1 ml) is added slowly, stirred for 5 min. then allowed to warm to ambient temp. and stirred for 45 min. The mixture is cooled to −72° C. and a zinc chloride solution (4.3 ml, 2.14 mmol, 0.5 M in toluene) added, warmed to ambient temp. and treated with 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 40 mg, 0.05 mmol). The mixture is heated to 65° C. overnight, cooled to ambient temp., added to water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 50% ethyl acetate in hexane) to elute the product. The title compound is obtained (0.7% yield). ES-MS (m/z): calc'd for C18H25N5: 311.4; found 312.2 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 7.51 (s, 1H), 6.75 (s, 1H), 3.72 (s, 3H), 3.33 (m, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 2.00 (s, 3H), 1.87 (m, 4H), 0.92 (m, 6H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([NH2:14])=[C:9]([F:15])[CH:8]=1.[CH:16]([NH:19][C:20](=O)[CH3:21])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([NH:14][C:20](=[N:19][CH:16]([CH3:18])[CH3:17])[CH3:21])=[C:9]([F:15])[CH:8]=1
Reactant: CC(=O)NC(C)C
Reactant: Nc1c(F)cc(Br)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=NC(C)C)Nc1c(F)cc(Br)cc1F
Temperature: 15 °C
Yield: 84.7 %

Procedure:
Add phosphoryl chloride (16.0 kg) to a mixture of 4-bromo-2,6-difluoro-phenylamine (14.5 kg), N-isopropyl acetamide (8.5 kg), TEA (10.6 kg) in toluene (115 kg) at <20° C. Stir at 10-20° C. until complete by HPLC. Remove the solvent under vacuum and add MtBE (64 kg). Adjust the pH of the mixture with 10% aq. sodium carbonate (250 kg). Filter the mixture and rinse the cake with MtBE (11×2 kg). Separate the phases and wash the aqueous layer with MtBE (22×2 kg). Combine the organic layers and concentrate, filter and wash with cyclohexane (0.6 kg) and dry to afford 17.2 kg of the title compound. MS (ES+): m/z=292 (M+H)+.