Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][C:2]2=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[H][H]>C(O)C.[Pt]=O>[CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCC=C1CCC2CCC1C2
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: O=C(O)CCCCC1CCC2CCC1C2

Procedure:
A solution of 3.4 g (16.3 mmol) of 5-(bicyclo[3.2.1]-oct-2-ylidene)pentanoic acid in 100 ml of absolute ethanol was hydrogenated at 50 psi over 300 mg of platinum oxide in a Parr apparatus. After 1.5 hr hydrogen uptake became slow. After 4 hr the system was flushed with nitrogen, and the catalyst was removed by filtration through diatomaceous earth filter aid (Celite). The filtrate was evaporated in vacuo to yield 3.25 g (96%) of quite pure 5-(bicyclo[3.2.1]oct-2-yl)pentanoic acid as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH3:15])[C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:19][OH:20]>>[OH:20]/[N:19]=[C:1](/[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH3:15])[C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)\[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C#N)n2C)cc1
Reactant: NO
Agent: Cl
Product: C/C(=N\O)c1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared from 5-(4-acetylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile and hydroxylamine hydrochloride salt according to the procedure described in example 1. MS (ESI) m/z 240; HRMS: calcd for C14H13N3O+H+, 240.11314; found (ESI, [M+H]+), 240.1126.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH2:17][CH3:18])=[O:7]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C=Cc1ccccc1F
Yield: 96 %

Procedure:
A solution of 2-fluorocinnamic acid (48.4 g, 0.29 mol, Aldrich) and thionyl chloride (5 mL) in ethanol (650 mL) was heated to reflux for 48 h. The mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed successively with a 5% aqueous sodium bicarbonate solution, water and brine, and dried (Na2SO4). Filtration and concentration gave 54.25 g (96%) of crude ethyl 2-fluorocinnamate. This material was used without further purification.
Reaction SMILES: [K+].[C:2]([C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[CH:5][C:6]([O-:8])=[O:7])#N.S(=O)(=O)(O)[OH:19]>C(O)=O.O>[N+:15]([C:11]1[CH:10]=[C:9]([C:4]2[C:2](=[O:19])[O:7][C:6](=[O:8])[CH:5]=2)[CH:14]=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: N#CC(=CC(=O)[O-])c1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: O=CO
Product: O=C1C=C(c2cccc([N+](=O)[O-])c2)C(=O)O1

Procedure:
To a suspension of.3-cyano-3-(3-nitro-phenyl)-acrylic acid potassium salt (1.28 g) in formic acid (10 ml) and water (1 ml) was added sulfuric acid (1 ml), and the mixture was refluxed for 3 hours. After cooling, the mixte was poured into water. The resulting precipitate was collected by filtration and dried to give 3-(3-nitrophenyl)-furan-2,5-dione(0.69 g).
Reaction SMILES: [Cl:1][C:2]1([C:10]2([Cl:21])[C:14](Cl)=[C:13]([Cl:16])[C:12](Cl)([Cl:17])[C:11]2([Cl:20])[Cl:19])[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]1[Cl:9].S(=O)(=O)(O)[OH:23].Cl>>[Cl:1][C:2]1([C:10]2([Cl:21])[C:14](=[O:23])[C:13]([Cl:16])=[C:12]([Cl:17])[C:11]2([Cl:20])[Cl:19])[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]1[Cl:9]
Reactant: ClC1=CC(Cl)C(Cl)(C2(Cl)C(Cl)=C(Cl)C(Cl)(Cl)C2(Cl)Cl)C=C1
Reactant: O=S(=O)(O)O
Agent: Cl
Product: O=C1C(Cl)=C(Cl)C(Cl)(Cl)C1(Cl)C1(Cl)C=CC(Cl)=CC1Cl

Procedure:
A mixture of 337 grams of 1,2,4-trichlorophenylheptachlorocyclopentene and 301 grams of concentrated sulfuric acid was stirred and heated at 105° to 124° centigrade for 10 hours. A total of 47 grams of hydrogen chloride was evolved and collected. The reaction mixture was mixed with water, the organic layer was separated and washed with water until neutral, after which it was dried and distilled. The product was collected as a red-orange viscous oil which crystallized on standing. Boiling point was 174°-178° centigrade at 0.4 millimeter of mercury pressure. Yield was 262 grams.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][C:14](=[CH2:18])[C:15](=[O:17])[CH3:16].CCN(CC)CC>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9](=[O:10])[CH2:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: C=C(C)C(C)=O
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C(C)CC(=O)c1ccc(S(C)(=O)=O)cc1
Reaction time: 3 h
Yield: 4.3 %

Procedure:
To a stirred solution of 4-(methylsulfonyl)benzaldehyde (1.84 g, 10 mmol) in ethanol (8 mL) was added 3-methyl-3-buten-2-one (0.8 g, 9.5 mmol), 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.51 g, 1.9 mmol), and Et3N (2.65 mL, 19 mmol) at room temperature. After stirring for 3 hours, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to provide the subtitle compound (0.11 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:12]([N+:22]([O-])=O)[CH:11]=2)=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Fe].CCO>[NH2:22][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:25]
Reactant: CN(C)CCNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)CCNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N

Procedure:
The sub-title compound was prepared in accordance with the procedure in Example 2, step (b) using N-(4-bromophenyl)-4-(2-(dimethylamino)ethylamino)-3-nitrobenzamide (560 mg; 1.38 mmol), Fe (384 mg; 6.88 mmol), NH4Cl (aq, sat, 10 mL) and EtOH (10 mL).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[N:27][CH:28]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl>CO.O1CCOCC1>[N:29]1([C:26]2[N:27]=[CH:28][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:42])[F:43])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:24][CH:25]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(N5CCNCC5)nc4)cnn23)c1

Procedure:
tert-Butyl 4-(5-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-imidazo[1,2-b]pyridazin-7-yl}pyridin-2-yl)piperazine-1-carboxylate (64 mg, 0.11 mmol) in methanol (0.5 mL) was treated with 4 N HCl in dioxane (0.4 mL) at r.t. for 1 h. The volatiles were removed under reduced pressure. The residue was dried in vacuum to afford the desired crude product which was used directly in next step without further purification. LCMS (M+H)+: m/z=497.1.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].[C:23](=O)([O-])[O-].[Na+].[Na+].IC>CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:23])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 150 °C
Yield: 65.2 %

Procedure:
A mixture of 10-[(2RS)-1-ethylamino-2-propyl]-2-phenothiazinecarbonitrile (4.4 g), sodium carbonate (2.25 g) and iodomethane (0.9 cc in dimethylformamide (60 cc) is heated for 6 hours to a temperature in the region of 150° C. The reaction mixture is then concentrated to dryness under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. and the residue is taken up with distilled water (100 cc) and extracted with ethyl acetate (2×100 cc). The combined organic phases are extracted with N aqueous hydrochloric acid solution (2×50 cc). The combined aqueous phases are alkalinized with sodium hydroxide (d =1.33) to pH 13 and extracted with ethyl acetate (2×100 cc). The combined organic phases are washed successively with distilled water (50 cc) and with saturated aqueous sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[(2RS)-1-(N-Ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbonitrile (3 g) is thereby obtained in the form of an orange oil. PG,47
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH2:35][CH3:36])CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:3]=[CH:2]/[C:1](=[O:8])[C:36]2[CH:35]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: CCN(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C(=O)c3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 120 °C

Procedure:
1-Phenylpropenone (58 mg, 0.44 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (200 mg, 0.37 mmol), Pd(OAc)2 (4 mg), triethylamine (372 mg, 0.367 mmol), and acetonitrile (3 mL) are placed in a microwave vial and heated at 120° C. for 15 min. The mixture is filtered over Celite and washed with acetonitrile. The filtrate is evaporated to give the title compound which is used directly in the next step.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[N:18]=[N:19][CH:20]=[CH:21][CH:22]=1.ClC(OCC)=O>C(Cl)Cl>[CH3:16][C:17]1[N:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:15]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: c1ccc(-c2cc3ccccn3n2)cc1
Reactant: Cc1cccnn1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: Cc1nnccc1-c1c(-c2ccccc2)nn2ccccc12
Reaction time: 6 h
Yield: 32 %

Procedure:
To a mixture of 2-phenylpyrazolo[1,5-a]pyridine (5.00 g), 3-methylpyridazine (2.90 g) and methylene chloride (20 ml), was added a solution of ethyl chloroformate (5.57 g) in methylene chloride for 17 minutes under ice-cooling and stirred for an hour at the same temperature and then for 6 hours and 40 minutes at room temperature. To the reaction mixture was added methylene chloride (20 ml), and washed with a solution of potassium carbonate (10 ml) and a saturated aqueous solution of sodium chloride (10 ml) and dried over magnesium sulfate. The solvent was removed and chromatographed on silica gel (70 g) with a mixture of n-hexane and ethyl acetate (2:1). The fractions containing the object compound were combined and evaporated in vacuo and recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(3-methylpyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.36 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:11][CH:12]=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:47])[CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:16]=[C:13](/[CH:14]=[CH:27]/[C:26]([O:25][CH3:24])=[O:47])[CH:12]=[N:11][C:10]=1[NH:17][C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1csc(Nc2ncc(C=O)cc2OCc2ccccc2)n1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A 25 mL round-bottomed flask was charged with 5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)nicotinaldehyde (500 mg, 1.54 mmol) and THF (10 mL). Methyl(triphenylphosphoranylidene)acetate (668 mg, 2.00 mmol) was added and the reaction was stirred at room temperature for 1 hour. An additional 668 mg of methyl(triphenylphosphoranylidene)acetate was added and the reaction was stirred overnight. The solids were filtered off and the filtrate was purified on a silica gel column (1:1 EtOAc:Hexanes) to afford (E)-methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)acrylate (450 mg, 76.8% yield) as a yellow foam. 1H NMR (CDCl3) 8.69 (s, 1H), 8.07 (d, 1H), 7.65 (d, 1H), 7.42 (m, 5H), 7.25 (m, 1H), 6.45 (m, 1H), 6.30 (d, 1H), 5.15 (s, 2H), 3.81 (s, 3H), 2.33 (s, 3H). Mass spectrum (apci) m/z=382.0 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH:12]2[C:26](OC)=[O:27].[OH-].[Na+]>O1CCCC1>[OH:27][CH2:26][CH:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH3:7])[CH:10]=2)[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)Cc2ccc(OC)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CO)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium aluminium hydride (5.62 g; 148 mmol) is suspended in 50 ml of anhydrous tetrahydrofuran. A solution of the compound obtained in Step F (11.9 g; 37 mmol), dissolved beforehand in 50 ml of anhydrous tetrahydrofuran, is then added dropwise. The reaction mixture is then stirred at ambient temperature for 2 hours. A minimum of sodium hydroxide solution (2N NaOH) is added to the reaction mixture until the evolution of gas has ceased in order to form the precipitates of lithium and aluminium hydroxides. The precipitates are then filtered off and washed with tetrahydrofuran. The organic phase is evaporated under reduced pressure. The title compound is purified by chromatography on silica gel.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[S:28][C:29]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)=[N:30][N:31]=3)[CH:20]=2)[O:7][C@H:6]1[CH2:37][O:38]C(=O)C)(=O)C.C[O-].[Na+].[H][H]>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:37][OH:38])[O:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[S:28][C:29]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)=[N:30][N:31]=1
Reactant: CC(=O)OC[C@@H]1O[C@@H](c2ccc(Cl)c(Cc3nnc(-c4ccco4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [H][H]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3nnc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a solution of (2S,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-((5-(furan-2-yl)-1,3,4-thiadiazol-2-yl)methyl)phenyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate (187 mg, 0.31 mmol) from Step 3 in methanol (10 mL) was added sodium methoxide (25 wt % in methanol, 1.0 mL). The reaction mixture was stirred at ambient temperature for 2 h. Amberlite® IR120 hydrogen form was then added to neutralize the reaction mixture. The resin was filtered off and the filtrate was concentrated in vacuo. Purification by reverse phase preparative HPLC (Gilson®, SunFire™ Prep, 5 to 50% acetonitrile in water gradient) provided the title compound (78 mg, 0.18 mmol, 58%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([CH:13]([CH3:15])[CH3:14])=[CH:6][C:5]=1B(O)O)[CH3:2].Br[C:20]1[C:28]2[C:23](=[CH:24][N:25]=[C:26]([C:29](=[O:31])[CH3:30])[CH:27]=2)[S:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([CH:13]([CH3:15])[CH3:14])=[CH:6][C:5]=1[C:20]1[C:28]2[C:23](=[CH:24][N:25]=[C:26]([C:29](=[O:31])[CH3:30])[CH:27]=2)[S:22][CH:21]=1)[CH3:2]
Reactant: CCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Reactant: CC(=O)c1cc2c(Br)csc2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1c(-c2csc3cnc(C(C)=O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 90 °C
Yield: 91.5 %

Procedure:
2-Ethoxy-3,5-diisopropyl-phenyl-boronic acid (586 mg, 2.34 mmol) was dissolved in toluene (10 ml). 1-(3-Bromo-thieno[2,3-c]pyridin-5-yl)-ethanone (310 mg, 1.21 mmol), and tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol) followed by 2M sodium carbonate solution (2.34 ml) was added to this solution. This mixture was then heated to 90° C. overnight, then poured into brine (20 ml) and extracted with ethyl acetate (2×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The residue was then purified by chromatography (chromatotron, 4μ plate, 10% ethyl acetate in hexanes) to give a 1-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-thieno[2,3-c]pyridin-5-yl]-ethanone as a white solid (422.2 mg, 91%). 1H NMR (250 MHz, CDCl3): δ 9.14 (s, 1H), 8.38 (s, 1H), 7.80 (s, 1H), 7.13 (d, 1H, J=1.9), 6.98 (d, 1H, J=1.9), 3.33 (m, 1H), 3.28 (q, 2H, J=7.5), 2.87 (m, 1H), 2.74 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H), 0.85 (t, 3H, J=7.5). MS [EI+] 382 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:11])[C:2]=1[O:1][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]=[O:7]
Reactant: ClCc1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Yield: 88.4 %

Procedure:
A mixture of 4.6 g (30.6 mmol) of 4-hydroxy 3,5-dimethyl benzaldehyde (Example E), 4.4 g (35 mmol) of benzyl chloride and 4.8 g (35 mmol) of anhydrous potassium carbonate in 100 mL of acetonitrile, is stirred at reflux for 18 hours overnight. The reaction flask and the inorganic salts are washed with fresh acetonitrile and the solvent is removed on a rotary evaporator. A diethyl ether solution of the residue is washed with 2×25 mL of 1N potassium hydroxide solution, brine, dried (magnesium sulfate) and evaporated. Distillation through a short path apparatus affords 6.5 g of the title compound; bp 149°-152° C./0.50 mm (190°-195° C).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(Nc1ccccc1)c1cccc(Oc2ccccc2)c1
Yield: 94.3 %

Procedure:
Prepared according to the procedure of Example 1 Step A using 3-phenoxybenzoic acid (1.2 g, 5.5 mmol), oxalyl chloride (0.55 mL, 6.3 mmol), and aniline (1.0 g, 10.7 mmol) to afford the product (1.5 g); m.p. 111-112° C. after recrystallization from ethanol.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][C:5]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:42].Cl>C(Cl)Cl.O>[F:1][C:2]([F:29])([F:30])[C@H:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][CH:5]=[O:42]
Reactant: CO
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC#N)C(F)(F)F)c3)ncnc21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC=O)C(F)(F)F)c3)ncnc21
Temperature: -47.5 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a −70° C. solution of (3R)-4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (1.06 g, 0.00243 mol) (see, Example 93, Step 1) in DCM (10 mL, 0.2 mol) was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL). The resulting mixture was stirred for 3 h and allowed to warm during this time interval from −70 to −25° C., after which the reaction was cooled back at −70° C. Methanol (1.5 mL, 0.037 mol) was added, followed by 2.0 M HCl in water (15 mL). Insoluble material was then filtered from the reaction mixture. The organic filtrate was washed sequentially with: 2.0 M HCl in water, water and saturated aqueous NaCl. The washed organic phase was dried over sodium sulfate and was concentrated using a rotory evaporator to give 0.58 g of the crude product as a pale yellow foam/solid. The crude product was chromatographed with 0-80% ethyl acetate/hexanes to give the purified product (0.9 g) as a pale orange oil (47% yield).
Reaction SMILES: CS(C)=O.[N:5]1([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](N2C=CN=C2)=[O:16])[CH2:9][CH2:8][CH2:7][CH2:6]1.O1CCCC1.[CH3:27][O:28][C:29]([C:31]1[C:32]([O:37][CH2:38][C:39]2[C:44]([F:45])=[CH:43][C:42]([Br:46])=[CH:41][C:40]=2[F:47])=[N:33][S:34][C:35]=1[NH2:36])=[O:30].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH3:27][O:28][C:29]([C:31]1[C:32]([O:37][CH2:38][C:39]2[C:40]([F:47])=[CH:41][C:42]([Br:46])=[CH:43][C:44]=2[F:45])=[N:33][S:34][C:35]=1[NH:36][C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:16])=[O:30]
Reactant: COC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1N
Reactant: O=C(NCCCCN1CCCC1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)NCCCCN1CCCC1
Temperature: 20 °C
Reaction time: 21.5 h
Yield: 90 %

Procedure:
Dimethylsulfoxide (105 mL, 5 volumes) was added to the imidazole-1-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide/tetrahydrofuran mixture, the tetrahydrofuran was removed by distillation under vacuum. The mixture was cooled to 20° C. then 5-Amino-3-(4-bromo-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylic acid methyl ester (1.00 equiv, 21.0 g) was added, followed by potassium carbonate (2.0 equiv, 15.2 g). The mixture stirred at 20° C. for 21.5 hours. Ethyl acetate (210 mL, 10 volumes) then water (210 mL, 10 volumes) were added. The slurry was stirred at 20° C. for 3-4 hours. The solids were filtered and the filter cake was rinsed with ethyl acetate (63.0 mL, 3 volumes). The solids were dried in a vacuum oven for 17 hours to give 27.36 grams of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid methyl ester (90% yield). 1H NMR: (DMSO-d6) δ 10.38 (s, 1H); 8.11 (m, 1H); 7.54 (m, 2H); 5.30 (s, 2H); 3.70 (s, 3H); 3.12 (m, 2H); 2.48 (m, 6H); 1.63 (m, 4H); 1.44 (m, 4H). MS (API-ES pos): 547/549 (M+H)+, base.