Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:30]=[CH:31]/B2OC(C)(C)C(C)(C)O2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH3:29][O:28][C:26]1[CH:25]=[C:24](/[CH:30]=[CH:31]/[C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:5]3=[N:6][CH:7]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: COc1cc(/C=C/B2OC(C)(C)C(C)(C)O2)cc(OC)c1
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Br)cnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(/C=C/c2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 88 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A stirred mixture of 2-bromo-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (929 mg, 2.75 mmol), 2-[(E)-2-(3,5-dimethoxyphenyl)vinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (from Aldrich, cat#676160, 838 mg, 2.89 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (140 mg, 0.171 mmol), and potassium phosphate (1.20 g, 5.65 mmol) in 1,4-dioxane (20 mL)/water (9.6 mL) was heated at 88° C. After 1 hour, the reaction mixture was quenched with saturated aq. NH4Cl and extracted with methylene chloride. The combined organic layers were dried over MgSO4, filtered, and then concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (1.10 g, 95%). LCMS calculated for C22H20N3O4S (M+H)+: m/z=422.2. Found: 422.2.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23]([OH:26])(=O)=[O:24])=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:30])=O.CN(C=O)C>C1COCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23]([Cl:30])(=[O:26])=[O:24])=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)O)ccc1OCC2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 208.1 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonic acid (228 mg, 0.61 mmol) in THF (15 mL) was added oxalyl chloride (257 μL, 3.04 mmol) and the resulting mixture stirred at RT for 15 min. The reaction mixture was cooled to 0° before DMF (126 μL, 1.69 mmol) was added and the resulting mixture warmed to RT after 10 min then stirred for a further 2 h. The reaction mixture was azeotroped with toluene affording 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride (500 mg).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7](/[CH:9]=[CH:10]/[C:11]2[C:12]([O:22]COC)=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2].[ClH:26]>CO>[ClH:26].[CH:1]([C:4]1[S:5][CH:6]=[C:7](/[CH:9]=[CH:10]/[C:11]2[C:12]([OH:22])=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2]
Reactant: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C(C)C)n1
Agent: Cl
Solvent: CO
Product: CC(C)c1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
To a solution of 2-isopropyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole (1.47 g) in methanol (20 mL) was added concentrated hydrochloric acid (0.5 mL) at room temperature, and the mixture was stirred at room temperature for 20 hrs. The reaction mixture was evaporated under reduced pressure, and the residue was washed with ethyl acetate-hexane to give 4-[(E)-2-(2-isopropyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol hydrochloride (1.43 g, yield 99%) as pale-yellow crystals. melting point: 137-139° C.
Reaction SMILES: Br.Br.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:5].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH3:5][N:4]([CH2:6][C:7]1([C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:3]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CN(C)CC1NCCc2c(O)cccc21
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)CC1(C(=O)Cc2ccc(Cl)c(Cl)c2)NCCc2c(O)cccc21

Procedure:
Prepared as Ex. No. 5, from 4.5 g (12.2 mmoles) of 1-dimethylaminomethyl-5-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 3.3 g (16.10 mmoles) of 3,4-dichlorophenylacetic acid, 4.3 ml (30.60 mmoles) of triethylamine and 5.1 g (24.75 mmoles) of dicyclohexylcarbodiimide in 120 ml of dry chloroform.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([CH:29]=O)[CH:20]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:29][C:21]2[CH:20]=[N:19][C:28]3[C:23]([CH:22]=2)=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cnc2ccccc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available quinoline-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.55 min.; [M+H]+: 363.35 g/mol.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:2]([OH:1])([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:9])[CH3:10])(=[O:7])=[O:6])=[CH:17][CH:16]=1
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(N)cc1
Reaction time: 3 h
Yield: 41.9 %

Procedure:
900 mg of [2-hydroxy-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine and 1.2 equivalence of 10% Pd/C in ethyl acetate (50 mL) were subjected to a hydrogen atmosphere while shaking at 60 psi for 3 hours. Solution was filtered through a Celite® mat and the resulting filtrate was concentrated under reduced vacuum to yield 720 mg as an oil. This material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 1:1 to yield the intermediate title compound (340 mg, 42%) as a tan solid. Ion spray M.S. 271.4 (M*−1).
Reaction SMILES: [C:1]1([N:7]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:8][CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][N:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[C:1]1([N:7]([S:39]([C:42]2[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=2)(=[O:41])=[O:40])[CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][N:15]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCN(CCCN(c2ccccc2)S(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)c2ccccc2)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N(CCCNCCCN(c2ccccc2)S(=O)(=O)c2ccc(C)cc2)c2ccccc2)cc1

Procedure:
Dissolve 1,9-bis[(phenyl)]-1,9-bis[(4-methylphenyl)sulfonyl]-5-(t-butyloxycarbonyl)-1,5,9-triazanonane (691 mg, 1 mmol) in saturated methanolic hydrochloric acid (10 mL). Stir for several hours and evaporate the solvent in vacuo. Dissolve the residue in water and neutralize with saturated sodium hydrogen carbonate and extract with ethyl acetate. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: Cl.[C:2]1([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C(N(CC)CC)C.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>CCOC(C)=O>[C:2]1([CH:8]([CH3:11])[CH2:9][NH:10][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(CN)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(CNC(=O)c1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 250-mL round-bottomed flask was charged with 2-phenylpropan-1-amine hydrochloride (7.75 g, 45.1 mmol), DCM (75 mL) and cooled down to 0° C. Triethylamine (13.8 mL, 99.3 mmol) was added followed by slow addition of 4-(trifluoromethyl)benzoyl chloride (7.4 mL, 49.7 mmol). After the addition was completed the mixture was stirred at RT for 1 h, diluted with EtOAc, washed with 10% HCl, sat NaHCO3, sat NaCl and dried over Na2SO4. The white residue was recrystallized from ether:hexanes and the title compound was obtained as a white solid. MS (ESI, positive ion) m/z: 308 (M+H).
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH:6]1([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])[CH2:8][CH2:7]1.Cl>CCOCC.O1CCCC1>[CH3:12][C:11]([OH:13])([CH2:10][CH2:9][CH:6]1[CH2:8][CH2:7]1)[CH2:4][C:3]#[CH:2]
Reactant: C#CCBr
Reactant: CC(=O)CCC1CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC(C)(O)CCC1CC1
Temperature: 25 °C

Procedure:
To 1 part by volume of magnesium in 25 parts by volume of tetrahydrofuran under argon is added a small amount of propargyl bromide and mercuric chloride to initiate reaction. Once the reaction is started 6.3 parts of propargyl bromide and 36 parts of 4-cyclopropyl-2-butanone in 50 parts by volume of tetrahydrofuran is added dropwise so as to maintain reflux. Upon completion of the reaction, the reaction mixture is cooled to room temperature and poured into a mixture of ether and 1N HCl. The aqueous layer is extracted twice with ether. The ether extracts are combined and washed 3 times with water and one time with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to provide a residual oil. The residual oil is distilled under high vacuum to provide 4-methyl-4-hydroxy-6-cyclopropyl-hex-1-yne.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1ccc(C(=O)CCCCl)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (5.00 g, 22.2 mmol) and N-bromosuccinimide (4.1 g, 23.0 mmol) in carbon tetrachloride (25 mL) and add AIBN radical initiator (300 mg). Stir and maintain under a nitrogen atmosphere at 80-90° C. or optionally irradiate with a sunlamp until a vigorous exotherm occurs at which point momentarily remove until reflux subsides and then reapply the heat. Reflux for 30 minutes and add another potion of N-bromosuccinimide (100 mg) while maintaining reflux and reflux an additional 15 minutes. Cool to room temperature and precipitate the succinimide from the solution by -allowing to stand overnight. Filter and wash the succinimide (2.25 g) with carbon tetrachloride (20 mL). Combine the filtrates and evaporate the solvent in vacuo to give the title compound as a yellow oil (6.80 g, 100%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[O:4].[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)=[O:4])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CCl)Nc1cccc([N+](=O)[O-])c1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1cccc([N+](=O)[O-])c1

Procedure:
The title compound is prepared from 2-chloro-N-(3-nitro-phenyl)-acetamide [Tetrahedron Lett. 39, 7459. (1998)] and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 102-104° C. (diethylether)
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1>O1CCCC1>[F:25][C:26]([F:34])([F:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH3:16])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:29][CH:28]=1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-fluorophenoxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.75 g of α,α,α-trifluoro-p-cresol in 75 ml of tetrahydrofuran at 80° C. for 18 hrs to give the product as a pale amber gum.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]3[N:15]=[C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][N:17]4[CH:23]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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].C(Cl)Cl>[F:22][C:20]1[CH:19]=[CH:18][N:17]2[CH:23]=[C:14]([CH2:13][CH2:12][N:8]3[C:9](=[O:11])[C:10]4[C:2]([C:27]5[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=5)=[CH:3][S:4][C:5]=4[CH:6]=[N:7]3)[N:15]=[C:16]2[CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: O=c1c2c(Br)csc2cnn1CCc1cn2ccc(F)cc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1c2c(-c3ccncc3)csc2cnn1CCc1cn2ccc(F)cc2n1
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-bromo-5-(2-(7-fluoroimidazo[1,2-a]pyridin-2-yl)ethyl)thieno[2,3-d]pyridazin-4(5H)-one (80 mg, 0.203 mmol), pyridin-4-ylboronic acid (37.5 mg, 0.305 mmol), PdCl2(dppf)-CH2Cl2 adduct (16.61 mg, 0.020 mmol) and Cs2CO3 (133 mg, 0.407 mmol) in 1,4-dioxane (3 mL) and water(1.5 mL) was heated under microwave at about 110° C. for about 15 min. The mixture was concentrated and was chromatographed on the ISCO Combiflash system using a 40 g Silicycle SiliaSep Silica gel column C-18 column using the following gradient: A: Water (0.1% NH4HCO3); B: Methanol; 30% B to 80% B over 20 min (15 mg, 18.8%).
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([SH:13])[CH:9]=[CH:10]2)=[CH:5][CH:4]=1.[O:14]1[CH2:16][CH:15]1[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.O>CN(C)C=O.O1CCCC1>[CH:7]1[C:6]2[C:11](=[CH:12][CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][C:8]=1[S:13][CH2:16][CH:15]([OH:14])[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1cncc(CCC2CO2)c1
Reactant: Sc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)CSc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.05 g) was added to a solution of 2-thionaphthol (0.174 g) in dry dimethylformamide (3 ml). A solution of (±)-3-(2-oxiranylethyl)pyridine (0.15 g) in tetrahydrofuran (1 ml) was added and the reaction mixture stirred for three hours at ambient temperature. The solution was poured into water which was extracted with ethyl acetate. The organic extracts were separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography on silica eluting with ethyl acetate to give the title compound as a white solid (0.15 g).
Reaction SMILES: NC1N=C(N)C2C(CN(C3C=CC=CC=3)C3C=CC=CC=3)=CSC=2N=1.[NH2:26][C:27]1[N:28]=[C:29]([NH2:37])[C:30]2[C:35]([CH3:36])=[CH:34][S:33][C:31]=2[N:32]=1.[CH:38]1[C:51]2[NH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[S:43][C:42]=2[CH:41]=[CH:40][CH:39]=1>>[NH2:26][C:27]1[N:28]=[C:29]([NH2:37])[C:30]2[C:35]([CH2:36][C:48]3[CH:47]=[CH:46][CH:45]=[C:44]4[C:49]=3[NH:50][C:51]3[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=3[S:43]4)=[CH:34][S:33][C:31]=2[N:32]=1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: Cc1csc2nc(N)nc(N)c12
Agent: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)csc2n1
Product: Nc1nc(N)c2c(Cc3cccc4c3Nc3ccccc3S4)csc2n1

Procedure:
9-[(2,4-Diaminothieno[2,3-d]pyrimidin-5-yl)methyl]phenothiazine (Formula I: Ar=2,4-diaminothieno[2,3-d]pyrimidin-5-yl; W=CH2; X=N; Z=S; m=n=0) is prepared similarly to N-[(2,4-diaminothieno[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed in Example 11 above by using 2,4-diamino-5-methylthieno[2,3-d]pyrimidine (1.3 g, 7.4 mmol) in Step 1 and phenothiazine (159 mg, 0.8 mmol) in Step 3. The final product and its intermediates can be purified by chromatography.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5](=O)[CH:6]([O:9][CH3:10])[O:7][CH3:8].[NH2:13][C:14]([NH2:16])=[S:15].C[O-].[K+]>CC(O)C>[CH3:8][O:7][CH:6]([O:9][CH3:10])[C:5]1[CH:4]=[CH:3][NH:16][C:14](=[S:15])[N:13]=1
Reactant: NC(N)=S
Reactant: COC(OC)C(=O)C=CN(C)C
Agent: C[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COC(OC)c1cc[nH]c(=S)n1
Yield: 73 %

Procedure:
The product from step 1 (4.8 g), thiourea (2.53 g) and potassium methylate (2.33 g) were heated together in boiling propan-2-ol (30 cm3) for 6 hours. The reaction mixture was allowed to cool overnight. The solvent was removed by evaporation under reduced pressure, the residue was dissolved in water and washed with ethyl acetate, the organic layer being discarded. The basic aqueous layer was acidified to pH 5 using glacial acetic acid and the product was extracted into ethyl acetate. Evaporation of the ethyl acetate under reduced pressure gave 3.769 g of an orange oil. 1H NMR (DMSO): δ3.46(6H,s); 5.14(1H,s); 6.94(1H,d); 7.18(1H,br s); 8.18(1H,d).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]=12.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]=12
Reactant: CCOC(=O)c1cnc2c(c1O)CCCCCCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(c1Cl)CCCCCCCC2

Procedure:
A mixture of 4.0 g of ethyl 4-hydroxy-5,6,7,8,9,10,11,12-octahydrocyclodeca[b]pyridine-3-carboxylate and 25 ml of phosphorus oxychloride is refluxed under argon for 3 hours and then evaporated to dryness under reduced pressure. A solution of the residue in methylene chloride is treated with ice and water and basified with 10N sodium hydroxide. The layers are separated, the aqueous phase is re-extracted with methylene chloride; the combined organic extract is dried with magnesium sulfate, filtered, and the solvent is removed at reduced pressure to yield ethyl 4-chloro-5,6,7,8,9,10,11,12-octahydrocyclodeca[b]pyridine-3-carboxylate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:6]([NH2:13])=[CH:5][CH:4]=1.C1N=CN([C:19](N2C=NC=C2)=[S:20])C=1>C(Cl)Cl>[N:13]([C:6]1[C:7]2[CH:8]=[C:9]([CH3:12])[O:10][C:11]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:19]=[S:20]
Reactant: COc1ccc(N)c2cc(C)oc12
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1ccc(N=C=S)c2cc(C)oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
7-Methoxy-2-methyl-4-nitro-benzofuran (1.24 g, 6.0 mmol) was hydrogenated using Pd/C (10%, dry, 700 mg) and H2 balloon in EtOH (30 mL) at r.t. for 2 h. The reaction mixture was filtered. Purification of the concentrated filtrate by column chromatography (EtOAc:Hexane=2.5:7.5) afforded 7-methoxy-2-methyl-benzofuran-4-ylamine as a brown oil (620 mg, 58%). 7-Methoxy-2-methyl-benzofuran-4-ylamine (620 mg, 3.5 mmol) was dissolved in CH2Cl2 (10 mL). TCDI (thiocarbodiimidazole, 686 mg, 3.9 mmol) was added to the solution and the reaction mixture was stirred at r.t. for 30 min. Silica gel was added to the reaction mixture and the solvent was removed under vacuum. Purification of the silica gel coated crude product by flash column chromatography (EtOAc:Hexane=2:8) afforded the title product as a pale yellow oil (630 mg, 82%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([OH:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](F)[C:25]=1[Cl:31].CCO>CN(C=O)C.Cl>[Cl:23][C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[O:20][C@@H:13]([CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@@H](O)C2CCOCC2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Clc1cccc(O[C@@H](C2CCOCC2)[C@@H]2CCNC2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-3-[(S)—Hydroxy(tetrahydropyran-4-yl)methyl]pyrrolidine-1-carboxylic acid t-butyl ester (30 mg, 0.1 mmol) was dissolved in DMF (380 μL). NaH (3.0 mg, 126 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluorobenzene (34.7 mg, 210 μmol) was added and the mixture was stirred at 100° C. overnight. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (510 μL, 610 μmol) and stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (10.8 mg, purity 100%). MS m/z: [M+H]+ calcd for C16H21Cl2NO2, 330.10. found 330.0.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH3:10][O:9][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])=[O:8]
Reactant: COC(=O)c1sccc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.8 %

Procedure:
To a solution of 5.00 g (0.032 mol) of 3-amino-2-carbomethoxythiophene dissolved in 40 mL of chloroform was added 7.73 mL (0.032 mol) of pyridine followed by 6.57 g (0.032 mol) of p-methoxybenzenesulfonyl chloride. The reaction mixture was stirred at room temperature for 5 h and then washed with 3N HCl and water. The organics were then dried over Na2SO4, filtered and concentrated in vacuo. The resulting cream colored solid was washed with ether and dried in vacuo to provide 6.89 g (66%) of the desired sulfonamide. Electrospray Mass Spec 328.2 (M+H).