Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:28][C:27]([CH2:29][CH2:30][CH3:31])=[N:26][C:14]=3[C:15]([NH:19]C(=O)C(Cl)(Cl)Cl)=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[S:28][C:27]([CH2:29][CH2:30][CH3:31])=[N:26][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3cc(OCc4ccccc4)ccc3c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2s1

Procedure:
To a magnetically stirred mixture of N-(7-benzyloxy-2-propylthiazolo[4,5-c]quinolin-4-yl)-2,2,2-trichloroacetamide (prepared as described above in Part H, 6.96 g, 14.9 mmol) in methanol (100 mL) at rt was added NaOMe (25 wt. % solution in MeOH, 11.3 mL, 52.1 mmol). After a few minutes a solution formed from which a solid precipitated. The reaction mixture was concentrated in vacuo and dried under vacuum. The resulting solid was suspended in a minimal amount of methanol (50 mL) and was isolated by filtration. The solid was washed with methanol to provide 7-benzyloxy-2-propylthiazolo[4,5-c]quinolin-4-amine as a light yellow solid in high purity (3.93 g, 76%), mp 175-178° C. 1H NMR (300 MHz, d6-DMSO) δ 7.67 (d, J=8.7 Hz, 1H), 7.49-7.29 (m, 5H), 7.10 (d, J=2.5 Hz, 1H), 6.96 (dd, J=8.7, 2.5 Hz, 1H), 6.84 (s, 2H), 5.20 (s, 2H), 3.09 (t, J=7.8 Hz, 2H), 1.84 (sextet, J=7.2 Hz, 2H), 0.99 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, d6-DMSO) δ 169.1, 158.9, 152.4, 146.5, 139.4, 137.0, 136.0, 128.4, 127.8, 127.6, 125.7, 113.3, 113.2, 107.8, 69.3, 35.1, 22.8, 13.5. MS (APCI) m/z=350.0 (M+H) % Anal. calcd for C20H19N3OS: C, 68.74; H, 5.48; N, 12.02. Found: C, 68.62; H, 5.74; N, 11.94.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][O:22]CC2C=CC=CC=2)[CH:16]=[CH:15][C:14]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]>C(O)C.[C].[Pd]>[O:1]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][OH:22])[CH:16]=[CH:15][C:14]=1[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH3:38])=[CH:35][CH:36]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCc1ccc(Cc2ccc(OCCOCc3ccccc3)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(Cc2ccc(OCCO)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of 5-[2-(benzyloxy)ethyloxy]-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside (0.022 g) in ethanol (1 mL) was added 10% palladium-carbon powder (0.0082 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=6/1) to give 2-(4-ethylbenzyl)-5-(2-hydroxy-ethyloxy)phenyl β-D-glucopyranoside (0.013 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: Brc1cncnc1
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccc(-c2cncnc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 42.7 %

Procedure:
To a suspension of 5-bromopyrimidine (1.59 g), 4-methyl-3-nitrophenylboronic acid (2.35 g) and tetrakis(triphenylphosphine)-palladium (578 mg) in 1,2-dimethoxyethane (20 ml) was added an aqueous solution of sodium carbonate (2M, 13 ml) followed by stirring at 80° C. for 24 hours. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol. The resulting precipitated was collected by filtration, washed with methanol and diisopropyl ether and dried to give 5-(4-methyl-3-nitrophenyl)-pyrimidine (918 mg, 84.2%).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:40])[C:29]3[N:33]=[C:32]([C@H:34]4[CH2:38][CH2:37][CH2:36][O:35]4)[NH:31][C:30]=3[CH:39]=2)[CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:40][C:28]1[C:29]2[N:33]=[C:32]([C@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[NH:31][C:30]=2[CH:39]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:27]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]c([C@H]3CCCO3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2[nH]c([C@H]3CCCO3)nc12

Procedure:
166 mg (0.65 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 205 mg (0.62 mmol) (R)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole and 320 μL (1.86 mmol) DIPEA in 5.0 mL DMF were stirred overnight at 50° C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C@H:6]([NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19](Br)[CH:18]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])C.C([O:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B1OC(C)(C)C(C)(C)O1)=[O:33])(C)(C)C.C([O-])([O-])=O.[K+].[K+].[OH-].[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.CCOC(C)=O.C1COCC1.CCO.C1(C)C=CC=CC=1>[C:4]([CH2:5][C@H:6]([NH:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:35]2[C:34]([C:32]([OH:33])=[O:31])=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:18]=1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])([OH:3])=[O:26]
Reactant: CC(C)(C)OC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)C[C@@H](Cc1ccccc1Cl)NC(=O)c1ccc(C)c(Br)c1
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2Cl)cc1-c1ccccc1C(=O)O
Temperature: 100 °C

Procedure:
(R)-3-(3-Bromo-4-methyl-benzoylamino)-4-(2-chloro-phenyl)-butyric acid ethyl ester (103 mg, 235 μmol, 1.0 eq.) was combined with 2-t-butoxycarbonylphenylboronic acid pinacol ester (85.9 mg, 282 μmol, 1.2 eq.). Toluene (328 μL) was added followed by EtOH (180 μL) then K2CO3 (65.1 mg, 471 μmol, 2.0 eq.) predissolved in water (61.5 μL). The mixture was stirred to aid in dissolution. The reaction vessel was purged with nitrogen then Pd(PPh3)4 (27.2 mg, 23.5 μmol) was added quickly. The reaction vessel was capped and heated to 100° C. for 30 minutes. The organics were removed and evaporated under vacuum. 1:1 TFA/DCM (0.2 mL each) was added and the resulting mixture was stirred for 30 minutes. The solvents were evaporated and THF (3 mL) and 1 M aqueous NaOH (706 μL, 3.0 eq.) were added. The mixture was stirred for 2 hours and EtOAc was added.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:12])[C:10]#[N:11].C(O)C.Cl>C1COCC1>[ClH:8].[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:12])[CH2:10][NH2:11]
Reactant: N#CC(F)c1ccc(Cl)cc1Br
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: NCC(F)c1ccc(Cl)cc1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve 2-(2-bromo-4-chlorophenyl)-2-fluoroacetonitrile (2.45 g, 9.86 mmol) in THF (50 mL). Cool the mixture to 0° C., then add BH3-THF complex (1 N, 20 mL, 20 mmol), and stir overnight. Add ethanol (5 mL) and then adjust to acidic with an ethanolic HCl solution. After removing the solvent, add DCM (20 mL) to the solid. Filter and wash with DCM, and dry to give the title compound as the HCl salt. MS (ES) m/z 254 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].CC1C=CC=CC=1C>[C:17]1([N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: O=Cc1ccc(N(c2ccccc2)c2cccc3ccccc23)cc1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
4-Bromobenzaldehyde (1.00 g, 5.40 mmol), 1-anilinonaphthalene (1.42 g, 6.48 mmol) and Pd(OAc)2 (25 mg, 0.11 mmol) and NaOtBu (623 mg, 6.48 mmol) were charged in a sealed tube. The sealed tube was deoxygenated and purged with nitrogen, and added dried o-xylene (30 mL) and tri-tert-butylphosphine (0.23 ml, 0.11 mmol). The reaction was heated to 120° C., and stirred for 48 hours. The resulting was filtered to remove metal and then concentrated under reduced pressure and the residue was purified by column chromatography (hexanes/CH2Cl2=1/1) to afford F (1.10 g, 63%) as yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([NH2:20])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1([CH2:27][C:28](O)=[O:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[N:21]1([CH2:27][C:28]([NH:20][C:17]2([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)=[O:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: NC1(c2ccc(OCCCN3CCCCC3)cc2)CC1
Reactant: O=C(O)CN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCOCC1)NC1(c2ccc(OCCCN3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-cyclopropylamine (0.195 g, 0.72 mmol) and morpholin-4-yl-acetic acid (0.125 g, 0.86 mmol) are dissolved in DMF, and diisopropylethylamine added (0.15 mL), followed by EDC (0.165 g, 0.86 mmol) and HOBt (0.116 g, 0.86 mmol). The reaction mixture was stirred overnight at room temperature. The residue is purified by chromatography [SCX-MeOH wash, elute 2M NH3/MeOH; then Biotage 12M SiO2, elute 10% (25/5/1 CHCl3/MeOH/NH4OH)/90% (10% MeOH/CHCl3)] to give the title compound as a yellow oil. HRMS 402.2765 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:8]=2)[S:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2S1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc2S1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A solution of 600 mg (2.11 mmol) of 2,2,4,4-tetramethyl-6-bromothiochroman (Compound 33) in 1.5 ml of triethylamine was placed in a heavy-walled tube and degassed and then treated under argon with 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed again, then placed under argon and the tube was sealed. The mixture was heated at 100 degrees C. for 24 h, allowed to cool to room temperature and then treated with a further 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was then degassed, placed under argon and then heated in the sealed tube at 100 degrees C. for 96 h. The mixture was cooled to room temperature and extracted with 3 x 10 ml of ether. The organic extracts were combined, washed successively with 25 ml of water and 25 ml of saturated sodium chloride solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes followed by 3% ethyl acetate in hexanes) to give the title compound as a yellow, crystalline solid. PMR (CDCl3): & 0.23 (9H, s), 1.36 (6H, s), 1.39 (6H, s), 1.94 (2H, s), 7.17 (1H, dd, J-8.2 Hz, 1.8 Hz), 7.25 (1H, d, J-1.8 Hz), 7.30 (1H, d, J-8.2 Hz). MS exact mass, m/l 302.1519 (calcd. for C18H26S Si, 382.1524).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:34])[C:23]1[CH:32]=[C:31]([OH:33])[CH:30]=[C:25]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:47][C:48]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:49]=1[CH2:55][CH2:56]O>C1COCC1>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[C:31]([O:33][CH2:56][CH2:55][C:49]2[CH:50]=[CH:51][C:52]([Cl:54])=[CH:53][C:48]=2[Cl:47])[CH:32]=[C:23]([C:22]([O:21][CH3:20])=[O:34])[CH:24]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCc2ccc(Cl)cc2Cl)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.75 g of triphenylphosphine and 1 g of 5-Hydroxy-isophthalic acid dimethyl ester were dissolved in 17 ml of anhydrous THF. The solution was cooled to 0–10° C. and a solution of 1 ml DEAD in 1 ml anhydrous THF was added dropwise over 20 min. The reaction was warmed to RT and stirred for 45 min. A solution of 11.3 ml 2-(2,4-Dichlorophenyl)-ethanol in 1 ml anhydrous THF was added with cooling. The reaction was stirred at RT for 16 h, then the solvents were removed under reduced pressure. The residue was treated with n-heptane:ethyl acetate/1:1. The filtrate was dried under reduced pressure and the product was purified by silica gel chromatography, eluting with n-heptane:ethyl acetate/4:1 to n-heptane:ethyl acetate/3:1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:1]([C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: CC(=O)Nc1cccc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2nc(=O)c3ccccc3s2)c1
Yield: 1.8 %

Procedure:
A mixture of N-(3-cyanophenyl)acetamide (2.00 g, 13 mmol), methyl thiosalicylate (3.20 g, 19 mmol), triethylamine (2.30 g, 23 mmol) and toluene (15 ml) was heated and refluxed for 25 hours under a nitrogen flow. The solvent was concentrated under reduced pressure. After washing with isopropyl ether and ethanol, the residue was recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (0.07 g, 2%) as crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]([CH3:61])[S:57](Cl)(=[O:59])=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:57]([N:56]([CH3:61])[CH3:55])(=[O:59])=[O:58])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CN(C)S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 48 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and dimethylsulfamoyl chloride as starting materials in 48% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.40 (m, 2H), 9.02 (s, 1H), 8.31 (m, 2H), 8.21 (s, 1H), 7.68 (m, 1H), 7.30 (m, 1H), 7.07 (m, 1H), 3.58 (m, 2H), 2.99 (m, 4H), 2.85 (m, 2H), 2.72 (s, 6H), 2.32 (m, 2H), 1.91 (m, 1H), 1.77 (m, 2H), 1.25 (m, 2H). LCMS for C26H32ClN8O3S (M+H)+: m/z=571.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([I:10])[CH:3]=1.[N:11]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([I:10])[CH:3]=1)[NH:9][N:11]=[CH:8]2
Reactant: O=N[O-]
Reactant: Cc1cc(Br)cc(I)c1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cc(I)c2[nH]ncc2c1
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
4-bromo-2-iodo-6-methyl-phenylamine (31.08 g, 99.6 mmol) was dissolved in glacial acetic acid (400 mL) in a 1 L round bottom flask equipped with a stir bar. The flask was then charged in one portion with sodium nitrite (7.56 g, 109.6 mmol) dissolved in water (18.7 mL). The mixture was stirred for about 15 minutes then the solvents were removed by evaporation on a rotovap at a bath temperature of about 35° C. The residue was stirred with water (200 mL) for 15 minutes and the resulting solid was collected by filtration and dried to yield 5-bromo-7-iodo-1H-indazole (30.6 g, 95%) as a brownish-tan solid; (DMSO-d6, 400 MHz) δ 13.6 (bs, 1H), 8.24 (s, 1H), 8.04 (d, J=1.54 Hz, 1H), and 7.88 (d, J=1.54 Hz, 1H); RP-HPLC (Table 1, Method e) Rt=3.63 min; m/z: (M−H)− 322.8.
Reaction SMILES: C(S([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][N:7]=1)(=O)=O)C.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>S1(CCCC1)(=O)=O>[CH2:15]([S:12]([C:9]1[CH:10]=[CH:11][C:6]([O:26][C:19]2[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])=[N:7][CH:8]=1)(=[O:13])=[O:14])[CH3:16]
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)c(Cl)cc2Cl)nc1
Temperature: 170 °C
Yield: 19.2 %

Procedure:
In 70 ml of sulfolane were mixed 10.5 g of 2,5-bis(ethylsulfonyl)pyridine, 15.8 g of 2,4,5-trichlorophenol and 11.06 g of potassium carbonate. The mixture was warmed gradually to 170° C. and maintained at that temperature for 2 hrs. The reaction mixture was cooled and then poured into 300 g of ice containing 4 g of sodium hydroxide. The aqueous solution was extracted with ether. The organic layer was washed with water, dried over MgSO4 and concentrated. The product was purified using a Water's Prep LC 500 instrument with 10% ethyl acetate/90% hexane as eluent. Recrystallization from diethyl ether gave 2.8 g, (19% yield), of purified 5-(ethylsulfonyl)-2-(2,4,5-trichlorophenoxy)pyridine, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Si](CC)(CC)CC.C([Li])(C)(C)C.CCCCC.[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)#[N:25]>C1COCC1>[OH:31][CH:30]([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[C:29]1[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=1
Reactant: CC[Si](CC)(CC)c1nccn1C
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cn1cncc1C(O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
A solution of 1-methyl-2-(triethylsilyl)-1H-imidazole (3.35 g, 17.08 mmol) in THF (50 mL) at −78° C. was treated dropwise with 2.5M tert-butyllithium in pentane (22.4 mL, 17.1 mmol), stirred for 30 minutes, treated dropwise with a solution of 4-cyanobenzaldehyde (2.04 g, 15.56 mmol) in THF (10 mL), and stirred for 1 hour. The mixture was quenched with methanol (4 mL), treated with 1N HCl (40 mL), warmed to room temperature, adjusted to pH 12 with 30% NaOH, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was triturated with 4:1 hexanes/ethyl acetate to provide 2.95 g (89%) of the desired product. MS (DCI/NH3) m/z 214 (M+H)+; 1H NMR (CDCl3) δ 7.67 (d, 2H), 7.53 (d, 2H), 7.40 (s, 1H), 6.67 (s, 1H), 5.95 (s, 1H), 3.53 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1.[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[C:35]([O:34][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:36]=1
Reactant: COC(=O)CCCCCCCNc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)c1cccc(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCCCCCCN(C(=O)c1cccc(OCc2ccccc2)c1)c1ccc(OCc2ccccc2)cc1

Procedure:
As described in example 3(b), the reaction is carried out with 4.7 g (13 mmol) of 8-(4-benzyloxyphenyl-amino)-caprylic acid methyl ester, 3.3 (13 mmol) of 3-benzyloxy- benzoic acid choride, 1.5 g (15 mmol) of triethylamine and 100 cc. of ether. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O.CO>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(ccc3nnc(C)n32)n1CCc1ccccc1
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
Sodium hydride (6.4 mg, 0.16 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (15 mg, 0.080 mmol, Example 2, Step 5) in DMF (2.2 mL). After stirring for 10 minutes, 1-bromo-2-phenylethane (22 μL, 0.16 mmol, Aldrich) was added dropwise. After stirring for 1 hour, additional sodium hydride (3.2 mg, 0.080 mmol, 60% in mineral oil) and 1-bromo-2-phenylethane (11 μL, 0.080 mmol) were added. The crude reaction mixture was diluted with water and MeOH, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product as a light yellow powder (4.8 mg, 20%).