Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33]Cl)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[O:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH:41]=[CH:40][N:39]=[C:38]1[Na]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:37]4[CH:41]=[CH:40][N:39]=[CH:38]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[O:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cn(-c3cccc(OCCCl)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Reactant: [Na]c1ncc[nH]1
Solvent: CN(C)C=O
Product: COc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.8 g of 5-(4-benzyloxy-3-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo-[2,3-d]pyrimidine and 0.2 g of imidazolyl sodium are heated to 80° C. in 30 ml of DMF and the mixture is stirred for 5 h. It is then cooled to RT and concentrated. After chromatography on silica gel, 5-(4-benzyloxy-3-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 122°-124° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.ClS(N=C=O)(=O)=O.[CH2:19]([N:26]([CH2:31][CH:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:34][CH2:33]1)[S:27]([NH2:30])(=[O:29])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:19]([N:26]([CH2:31][CH:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:34][CH2:33]1)[S:27]([NH:30][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=1)(=[O:28])=[O:29])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CN(Cc2ccccc2)S(N)(=O)=O)CC1
Reactant: Cc1cc(C)cc(C(=O)O)c1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(C(=O)NS(=O)(=O)N(Cc2ccccc2)CC2CCC(CO[Si](C)(C)C(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 86 %

Procedure:
3,5-Dimethylbenzoic acid (1.50 g, 10.0 mmole, 1.0 eq) was suspended in 5 mL dichloromethane and heated to reflux, after which a solution of chlorosulfonyl isocyanate (0.87 mL, 10.0 mmole, 1.0 eq) in 2 mL dichloromethane was added. Reaction mixture became clear, and remained so after 40 minutes of reflux. Cooled to room temperature, added hexanes and began to evaporate when solid precipitated out. Recovered filtered solid. 23 mg, 92 μmole, 1.0 eq of this material was added to a mixture of intermediate (2) (34 mg, 92 μmole, 1.0 eq) and triethylamine (39 μL, 277 μmole, 3.0 eq) in dichloromethane (0.5 mL). Reaction was complete at 2 hours, at which point it was purified directly by silica gel chromatography to give the title compound in 86% yield. 1H NMR (500 MHz, DMSO-d6): δ 11.84 (s, 1H), 7.49 (s, 2H), 7.31 (m, 6H), 4.52 (s, 2H), 3.28 (d, 2H), 3.09 (d, 2H), 2.30 (s, 6H), 1.58 (m, 4H), 1.31 (m, 1H), 1.22 (m, 1H), 0.82 (s, 9H), 0.66 (m, 4H), 0.04 (s, 6H). N-benzyl-N′-(3,5-dimethylbenzoyl)-N-{[4-(hydroxymethyl)cyclohexyl]methyl}sulfamide (38): Intermediate (37) was treated as (3) was treated in the synthesis of (4) to give the title alcohol in quantitative yield. 1H NMR (500 MHz, DMSO-d6): δ 11.85 (s, 1H), 7.50 (s, 2H), 7.31 (m, 6H), 4.52 (s, 2H), 4.27 (t, 1H), 3.10 (m, 4H), 2.32 (s, 6H), 1.59 (m, 4H), 1.31 (m, 1H), 1.22 (m, 1H), 0.66 (m, 4H). {4-[(benzyl{[(3,5-dimethylbenzoyl)amino]sulfonyl}amino)methyl]cyclohexyl}methyl phenylcarbamate (39): Alcohol (38) (34.6 mg, 78 mmole, 1.0 eq) in 0.5 mL dichloromethane was treated with triethylamine (38 mL, 272 mmole, 3.5 eq) and phenyl isocyanate (17 mL, 156 mmole, 2.0 eq) to give the title compound after preparative TLC. 1H NMR (500 MHz, DMSO-d6): δ 11.85 (s, 1H), 9.52 (s, 1H), 7.50 (s, 2H), 7.41 (d, 2H), 7.36 (d, 2H), 7.30 (t, 2H), 7.24 (t, 3H), 7.19 (s, 1H), 6.95 (t, 1H), 4.48 (s, 2H), 3.800 (d, 2H), 3.07 (d, 2H), 2.32 (s, 6H), 1.64 (m, 4H), 1.47 (m, 1H), 1.34 (m, 1H), 0.73 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20].N.CO.[NH4+].[Cl-]>CO.O1CCOCC1>[ClH:16].[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[N:14]=1)=[O:20]
Reactant: CN1CCC(Oc2cccc(N)n2)CC1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCC(Oc2cccc(NC(=O)c3c(F)cccc3Cl)n2)CC1
Product: Cl
Temperature: 50 °C

Procedure:
Combine 6-(1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 60, 200 mg, 0.96 mmol), and dioxane (15 mL), stir and heat at 50° C. Add 2-chloro-6-fluorobenzoyl chloride (214 □L, 1.1 mmol), and heat at 85° C. for an additional 3 hr. Cool the reaction to room temperature, and load onto a 5 g SCX cartridge. Wash resin with Methanol, then remove product with 2 M NH3/methanol. Concentrate in vacuo, and silica gel chromatography eluting with 5-20% 2 M NH3 in methanol/methylene dichloride. Dissolve the purified oil (286 mg, 81% isolated yield) in methanol, add NH4Cl (42 mg, 1 eq) as a solid, and sonicate the solution at room temperature for 15 min. Concentration in vacuo provides the title compound: mass spectrum (ion spray): m/z=364.1 (M+1); mp=139.6° C.
Reaction SMILES: [C:1]([CH2:9][CH:10]([OH:14])[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]([CH2:17][CH:18]([OH:21])[CH2:19][CH3:20])[NH2:16]>C(O)CCC>[OH:14][CH:10]1[CH2:9][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:16][N:15]([CH2:17][CH:18]([OH:21])[CH2:19][CH3:20])[C:11]1=[O:13]
Reactant: O=C(CC(O)C(=O)O)c1ccccc1
Reactant: CCC(O)CNN
Solvent: CCCCO
Product: CCC(O)CN1N=C(c2ccccc2)CC(O)C1=O
Temperature: 120 °C

Procedure:
A mixture of 3.5 grams (18 mmol) of 3-benzoyl-2-hydroxy-propionic acid and 1.9 grams (18 mmol) of 1-hydrazino-2-butanol in 40 ml of n-butanol is refluxed under nitrogen at 120° C. for 18 hours. After evaporation of the solvent, the product is partitioned between ether and water. The ether layer is washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. The resulting residue is dissolved in 2% ethanol-chloroform and filtered through 200 grams of silica gel yielding after evaporation 4,5-dihydro-4-hydroxy-2-(2-hydroxybutyl)-6-phenylpyridazin-3(2H)-one, m.p. 92°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([O:11][CH2:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([N:14]1[C:22]2[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)[CH2:12][CH3:13])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CCO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(CCOS(C)(=O)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-(1-(3-(4-chlorophenyl)-1-hydroxypentan-3-yl)-1H-indol-4-yl)methanesulfonamide (20 mg, 0.05 mmol), as described in Example 40 Step I, and NMM (10 mg, 0.1 mmol) in DCM (3 mL) was added methanesulfonyl chloride (7 mg, 0.06 mmol). Then the mixture was stirred at room temperature for 1 h, quenched with saturated ammonium chloride solution (5 mL), and extracted with ethyl acetate. The organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by Prep-TLC (PE/EA=4/1) to afford the title compound as colorless oil. LC/MS m/z=485.1[M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:30][NH:29][N:28]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:29]3[CH:30]=[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:27]([CH3:26])=[N:28]3)=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1n[nH]cc1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3cc(-c4ccccc4)c(C)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.4 %

Procedure:
A mixture of 4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid (200 mg, 0.55 mmol), 3-methyl-4-phenylpyrazole (87 mg, 0.55 mmol), Copper(II) acetate (120 mg, 0.66 mmol), triethylamine (0.23 mL, 1.65 mmol), molecular sieves 4A (200 mg), and dichloromethane (8 mL) was stirred at room temperature for 3 days. After filtration through a bed of celite, the filtrate was diluted with dichloromethane, and washed with water. The organic fraction was dried over MgSO4. After concentration under reduced pressure, the residue was purified by TLC with dichloromethane/ethylacetate (10:1) to afford 56 mg (21%) of the title compound as white solids: MS (ESI) m/z 476 [M+H]+, 474 [M−H]−, 1H-NMR (CDCl3) δ 7.88 (2H, d, J=8.5 Hz), 7.61-7.19 (11H, m), 4.31 (2H, t, J=6.6 Hz), 2.92 (2H, t, J=6.6 Hz), 2.49 (3H, s), 2.42 (3H, s).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:44][N:45]([CH2:47][C:48]1[C:56]2[C:51](=[N:52][CH:53]=[C:54](/[CH:57]=[CH:58]/[C:59](O)=[O:60])[CH:55]=2)[NH:50][CH:49]=1)[CH3:46]>CN(C)C=O>[CH3:44][N:45]([CH2:47][C:48]1[C:56]2[C:51](=[N:52][CH:53]=[C:54](/[CH:57]=[CH:58]/[C:59]([N:11]3[CH2:12][CH:9]([O:8][CH2:7][C:3]4[S:2][CH:6]=[CH:5][CH:4]=4)[CH2:10]3)=[O:60])[CH:55]=2)[NH:50][CH:49]=1)[CH3:46]
Reactant: c1csc(COC2CNC2)c1
Reactant: CN(C)Cc1c[nH]c2ncc(/C=C/C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1c[nH]c2ncc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cc12
Reaction time: 8 h

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (61 mg, 0.30 mmol), EDCI (71.5 mg, 0.37 mmol), HOBt (52 mg, 0.37 mmol) and diisopropylethylamine (110 μL, 0.62 mmol) were successively added to a solution of (E)-3-(3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylic acid hydrochloride (70 mg, 0.25 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight then partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was separated, basified with an aqueous solution of sodium hydroxyde (2N) until pH 12 and finally extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×50 mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol/ammoniac (1:0:0.1 to 9:1:0.1) as eluent. The title product was obtained as a yellow solid (10 mg, 10%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:14])[CH3:13])[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:14])[CH3:13])[CH3:2]
Reactant: CCOC(=O)CCNC1CCCC1(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of 2.2 g (0.011 mole) of (rac)-3-(2,2-dimethyl-cyclopentylamino)-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-92:8) gave 3.3 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-59).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@@H:7]([C:18]([S:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=O)=[O:9])=[O:5])[CH3:2].[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([NH2:37])=[N:32][CH:31]=[CH:30]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CC(O)=O>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C@H:7]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15](=[O:17])[NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([NH2:37])=[N:32][CH:31]=[CH:30]2)=[O:9])[C:18]([S:21][CH:22]([CH3:23])[CH3:24])([CH3:20])[CH3:19])[CH3:2]
Reactant: NCc1ccc2c(N)nccc2c1
Reactant: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)(C)SC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)C(C)(C)SC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
A mixture of 1-[2-(R)-ethoxycarbonylamino-3-isopropylsulfanyl-3-methyl-butyryl]-pyrrolidine-2-(S)-carboxylic acid (0.160 g), 6-aminomethyl-isoquinolin-1-ylamine (0.078 g), N-methyl morpholine (0.14 mL) and 0.14 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 3 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. 0.100 mL CH3COOH were added, the mixture was concentrated and the remaining residue was purified by HPLC (RP-18; H2O/CH3OH 95/5→0/100) to give 0.17 g (66%) of the title compound as a colorless oil. (+)-APCI-MS: 516 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:6](=[CH2:7])[S:5][CH:4]([C:8]([O:10][CH3:11])=[S:9])[CH:3]=1.BrC1C=C(C(O)=S)SC=1C.S(Cl)(Cl)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7]
Reactant: C=C1SC(C(=S)OC)C=C1Br
Agent: Cc1sc(C(O)=S)cc1Br
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=S)c1cc(Br)c(C)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
Methyl 4-bromo-5-methlylthiothiophene-2-carboxylate: To a stirred solution of 4-bromo-5-methylthiothiophene-2-carboxylic acid (87 mmol), prepared according to the procedure of Kleemann, et al., EP 0676395A2, in dry methanol (750 mL) was added thionyl chloride (7 mL, 96 mmol) dropwise. After stirring for 10 min at room temperature, the solution was heated to reflux and stirred 7.5 h. The solution was cooled and the solvents were removed in vacuo. The resulting solid was dissolved in dichloromethane (1500 mL) and washed with saturated sodium bicarbonate (2×300 mL), water (300 mL), saturated brine (300 mL), and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. The resulting solid was recrystallized twice from hexane/ethyl acetate to give methyl 4-bromo-5-methylthiothiophene-2-carboxylate (4.4 g, 19%). 1H-NMR (CDCl3, 400 MHz) δ 7.66 (s, 1H), 3.90 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.CCN(CC)CC.[O:16](S(C(F)(F)F)(=O)=O)[S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[S:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][CH:3]=1)(=[O:18])=[O:16]
Reactant: Cc1ccc(O)cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(OS(=O)(=O)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5 g of 3-hydroxy-6-methylpyridine in 100 mL of CH2Cl2 at 0° C. was added successively 7.7 mL of Et3N and 8.1 mL of Tf2O. The reaction was stirred at room temperature for 30 minutes, then diluted with more CH2Cl2 (220 mL). The organic phase was washed successively with 1N HCl, brine, dried over MgSO4, filtered, and concentrated to give after purification using flash chromatography on silica gel (hexane:EtOAc 65:35) the title compound.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@@H:11]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=2)[CH2:12][C:13]([O:15][CH3:16])=[O:14])C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[OH:8][CH2:9][CH2:10][C@@H:11]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:28]([CH3:30])[CH3:29])[CH:31]([CH3:33])[CH3:32])=[CH:21][CH:20]=2)[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C[C@@H](CCOCc1ccccc1)c1cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H](CCO)c1cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2[nH]1
Yield: 92 %

Procedure:
To a solution of (R)-methyl 5-(benzyloxy)-3-(5-(triisopropylsilyloxy)-1H-indol-2-yl)pentanoate (52.5 g, 103 mmol in EtOAc (150 mL) was added 10% Pd/C (wet, 15 g) and placed in a Parr shaker under 45 psi of hydrogen for 2.5 h (dropped 10 psi during the 2.5 h). The mixture was filtered through celite and concentrated to give (R)-methyl 5-hydroxy-3-(5-(triisopropylsilyloxy)-1H-indol-2-yl)pentanoate (47.6 g, 93 mmol, 92% yield) as a viscous yellow oil. Exact mass calculated for C23H37NO4Si: 419.2, found: LCMS m/z=420.3, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.11 (d, J=7.2 Hz, 18 H), 1.27 (m, 3 H), 1.97 (m, 2 H), 2.75 (m, 2 H), 3.49 (m, 1 H), 3.69 (m, 5 H), 6.13 (d, J=2.0 Hz, 1 H), 6.73 (dd, J1=8.6, J2=2.3 Hz, 1 H), 6.99 (d, J=2.3 Hz, 1 H), 7.21 (d, J=8.6 Hz, 1 H), 8.58 (bs, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9](=[N:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.C(O[C:26](=[O:30])[CH2:27][C:28]#[N:29])C.C([O-])(=O)C.[NH4+]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:10]([CH3:11])=[C:27]([C:28]#[N:29])[C:26](=[O:30])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(NN=C(Sc2ccc(C)cc2)C(C)=O)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(-n2nc(Sc3ccc(C)cc3)c(C)c(C#N)c2=O)cc1
Temperature: 160 °C

Procedure:
An intimate, magnetically stirred mixture of 440 mg (1.40 mmol) of 1-[(4-methylphenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone 370 μl of ethylcyanoacetate and 178 mg of ammonium acetate was heated under a nitrogen atmosphere at 160° C. for 30 min. The reaction mixture was cooled and dissolved in methylene chloride. The organic layer was washed successively with saturated aqueous sodium bicarbonate and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to yield semi-pure product. The residue was recrystallized from ethanol to yield 6-[(4-methylphenyl)thio]-2,3-dihydro-2-(4-methoxyphenyl)-5-methyl-3-oxo-4-pyridazinecarbonitrile, mp 148-149° C.(EtOH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:23]=1>C1(C)C=CC=CC=1>[CH3:15][C:4]1[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=[C:2]([CH:22]=[CH2:23])[CH:3]=1)[C:7]#[N:8]
Reactant: Cc1cc(Br)cc(C#N)c1-n1cncn1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=Cc1cc(C)c(-n2cncn2)c(C#N)c1
Temperature: 25 °C
Yield: 1043.1 %

Procedure:
A mixture of 5-bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.6 g, 2.3 mmol), potassium carbonate (0.95 g, 6.87 mmol), vinyl boronic anhydride (0.82 g, 3.43 mmol) and triphenylphosphine (0.13 g, 0.114 mmol) in toluene (20.0 mL) were stirred and degassed with argon for 30 min. The reaction mixture was heated to reflux for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound that was purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) to afford the title compound as a pink solid (0.25 g, 52%): 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (d, J=17.6, 1H), 5.52 (d, J=10.8 Hz, 1H), 2.21 (s, 3H), ESIMS m/z 211.35 ([M+H]+); IR (thin film) 2236, 1511 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1.[O:22]=[C:23]1[CH2:28][S:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.CCO>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH2:33][C:31]2[CH:30]=[CH:29][C:26]3[S:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=3[N:32]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc2nccc(-c3ccc(CCN)cn3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc(-c3ccc(CCNCc4ccc5c(n4)NC(=O)CS5)cn3)c2n1
Reaction time: 24 h
Yield: 30.2 %

Procedure:
To a stirred solution of 2-[6-(6-methoxy[1,5]naphthyridin-4-yl)pyridin-3-yl]ethylamine (0.94 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (0.18 g, 0.94 mmole) and Na2SO4 (500 mg). After 24 h, the reaction contents were concentrated and dried under high vacuum. To a stirred solution of the crude imine in dry EtOH (25 mL) at RT was added NaBH4 (36 mg, 0.94 mmole). After 24 h, the reaction solution was concentrated under vacuum and to the residue was added 1M HCl (5 mL) and EtOAc (50 mL). After stirring for 1 h, 6M NaOH (1 mL) was added and the organic layer was separated, dried (Na2SO4) and concentrated. Purification on reverse-phase HPLC (CH3CN/H2O, 10-90%) afforded the title compound (0.13 g, 30%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.89 (br s, 1H), 9.15 (m, 1H), 8.90 (m, 1H), 8.57 (d, J=9.1 Hz, 1H), 8.45 (d, J=9.1 Hz, 1H), 8.20 (m, 2H), 7.51 (m, 1H), 7.22 (d, J=9.1 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 4.24 (m, 2H), 4.02 (s, 3H), 3.55 (m, 2H), 3.41 (m, 2H), 3.30 (s, 2H). LC-MS (ES) m/e 459 (M+H)+.