Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[NH2:22][C:16]1[N:15]=[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][N:28]([CH2:27][C:26]([CH3:42])([OH:43])[CH3:25])[CH:32]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Similar to as described in General Procedure C, 5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine was reacted with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol. Purification of the crude reaction mixture by reverse phase HPLC gave 368. LCMS: 466.2.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH:5](OC)[CH:6](OC)[CH2:7][C:8]([O:10]C)=[O:9].[OH-].[Na+]>O>[C:8]([OH:10])(=[O:9])/[CH:7]=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:16])=[O:2]
Reactant: COC(=O)CC(OC)C(CC(=O)OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)/C=C/C=C/C(=O)O

Procedure:
23.5 Grams (0.1 mole) of β, β'-dimethoxy-adipic acid-dimethylester were boiled under reflux with a solution of 32 g of NaOH in 50 ml of water for 8 hours, were cooled, suction-filtered, dissolved in water, were precipitated with concentrated hydrochloric acid at a pH value of 1, were washed with water until neutral and dried. 12.2 Grams (86 % of the theoretical yield) of trans, trans-muconic acid were obtained which had a melting point of from 298° to 300° C.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:27])=[C:16]([O:23][C:24](=[O:26])[CH3:25])[C:17](=[O:22])[N:18]2[CH3:21])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH3:28][O:29][CH2:30]Cl>C1COCC1>[N+:8]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:27][CH2:28][O:29][CH3:30])=[C:16]([O:23][C:24](=[O:26])[CH3:25])[C:17](=[O:22])[N:18]2[CH3:21])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CC(=O)Oc1c(O)c2ccc([N+](=O)[O-])cc2n(C)c1=O
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCOc1c(OC(C)=O)c(=O)n(C)c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
After addition of 1.87 g of triethylamine (18.5 mmol) to a mixture of 3.2 g of 7-nitro-3-acetoxy-4-hydroxy-1-methyl-2(1H)-quinolinone (11.5 mmol) in 64 ml of THF, 1.89 g of chloromethyl methyl ether (23.0 mmol) was dropped to the mixture, and stirred at room temperature for 1 hour. Filtration of the reaction mixture, the filtrate was concentrated under reduced pressure to give 3.6 g of 7-nitro-3-acetoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone. In accordance with EXAMPLE 4, the obtained 7-nitro-3-acetoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was used instead of 7-nitro-3-acetoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 7-nitro-3-hydroxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was provided. Then in accordance with EXAMPLE 2, 7-nitro-3-methoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was given by methylation reaction. Finally, to a mixture of the obtained 7-nitro-3-methoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone in 40 ml of methanol was added 0.22 g of p-toluenesulfonic acid monohydrate and stirred at room temperature for 1 hour. To the reaction mixture was added water, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was crystallized from THF and hexane to yield 1.45 g of the title compound (18). (yield=54%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:9](Br)[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.Cl[P:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:9]([P:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(Br)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)P(c1ccccc1)c1ccccc1
Temperature: -65 °C
Yield: 56.6 %

Procedure:
Into a reactor were introduced 0.907 g (2.93 mmol) of the 1,1-bis(4-fluorophenyl)-2-bromopropene and 20 mL of THF under a nitrogen atmosphere. The contents were cooled to −65° C., and 2.0 mL (2.9 mmol; 1.5 M hexane solution) of butyllithium was gradually added dropwise thereto. The resultant mixture was stirred for 40 minutes. Thereafter, a mixture of 0.58 mL (3.2 mmol) of chlorodiphenylphosphine and 5 mL of THF was added thereto, and the resultant mixture was stirred at that temperature for 2 hours and then heated to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The resultant organic layer was washed with water and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from methanol to obtain 0.687 g (57%) of the target compound as white crystals.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13]CC)=[O:12]>Cl>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1cnc2ncnn2c1O
Agent: Cl
Product: O=C(O)c1cnc2ncnn2c1O

Procedure:
A mixture of ethyl 7-hydroxy-1,2,4-triazolo[1,5-a]-pyrimidine-6-carboxylate (5.6g. 25mM) and 2N hydrochloric acid (40ml) was heated under reflux for 5 hours. The reaction mixture was cooled and filtered to give the required product in 67.3% weight yield (3.30g). m.p. 296° C (decomposition). νmax (KBr disc) 1725 (acid C=O)cm-1 ; λmax (NaHCO3 solution) 293nm (εm 14,900); (Found: C, 40.27; H, 2.35; N, 30.49%. C6H4N4O3 requires C, 40.01; H, 2.24; N, 31.10%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH:18]2[CH2:19][CH2:20][CH:9]1[CH2:10][C:11]1[CH:12]=[C:13]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]([F:33])([F:32])[F:31])[CH2:26][CH2:25]3)[CH:14]=[CH:15][C:16]=1[CH2:17]2)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:32][C:30]([F:31])([F:33])[CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][CH2:21][C:13]2[CH:14]=[CH:15][C:16]3[CH2:17][CH:18]4[CH:8]([NH2:7])[CH:9]([CH2:20][CH2:19]4)[CH2:10][C:11]=3[CH:12]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1C2CCC1Cc1cc(CCCN3CCC(C(F)(F)F)CC3)ccc1C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1C2CCC1Cc1cc(CCCN3CCC(C(F)(F)F)CC3)ccc1C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
The Boc protecting group was removed by dissolving the product of Step 3 (87 mg, 0.181 mmol) in 3:1 DCM-TFA (4 ml) and stirring at 0° C. for 1 hour. The mixture was concentrated to dryness, and a solution of the residue in DCM washed with sodium carbonate solution (sat). The organic phase was dried and evaporated to give a colourless oil 66 mg (96%). 1H NMR (CDCl3, 360 MHz) δ 6.99 (1H, d, J=8.4 Hz), 6.90 (2H, m), 3.36 (1H, t, J=6.1 Hz), 3.21 (2H, m), 2.99 (2H, m), 2.45–2.59 (4H, m), 2.35 (2H, m), 2.23 (2H, m), 1.57–2.04 (11H, m), 1.17 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([CH2:9][CH:10]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]=[C:23](Cl)[CH:22]=[C:21]([N:26]([CH3:33])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:20]=2)[CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[N:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:42])[N:7]([CH2:9][CH:10]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:20]=[C:21]([N:26]([CH3:33])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=[C:23]([C:52]3[CH:53]=[CH:54][N:49]=[CH:50][CH:51]=3)[N:24]=2)[CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CN(CC(COc1cccc(-c2nc(Cl)cc(N(C)C3CCOCC3)n2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(CC(COc1cccc(-c2nc(-c3ccncc3)cc(N(C)C3CCOCC3)n2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-chloro-6-[methyl-(tetrahydro-pyran-4-yl)-amino]-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (160 mg, 0.26 mmol) in degassed dioxane and H2O (4/1, 25 mL) was added Na2CO3 (83 mg, 0.78 mmol); Pd(PPh3)4 (30 mg, 0.026 mmol) and pyridin-4-ylboronic acid (64 mg, 0.52 mmol). The system was purged with N2 stream and the mixture was stirred 100° C. for 2 h., cooled down to room temperature, diluted with water (25 mL) and extracted with EtOAc (25 mL×2). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatographic column on silica gel (petroleum ether/EtOAc=10/1 to 1/1) to give [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-[methyl-(tetrahydro-pyran-4-yl)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (128 mg, 75% yield). ESI-LCMS (m/z): 664.4 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([S:12]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:7][C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])=[CH:5][C:4]=2[N:3]=1.C([O-])(=[O:30])C.[Na+]>C(O)(=O)C>[CH:16]1([NH:15][S:12]([C:8]2[C:9]3[CH:10]=[CH:11][C:2](=[O:30])[NH:3][C:4]=3[CH:5]=[C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:7]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(Cl)nc2c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(=O)[nH]c2c1

Procedure:
A mixture of 2-chloro-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide (350 mg, 0.86 mmol) and sodium acetate (700 mg, 10 equiv) in acetic acid (10 mL) was refluxed overnight. The mixture was partitioned between sodium bicarbonate solution and ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate solution and dried over sodium sulfate to give N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide as a white powder.
Reaction SMILES: Br.C([O:9][C:10]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[N:12]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:11]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])C1C=CC=CC=1>CC(O)=O.C(Cl)Cl>[CH2:16]([O:15][C:14]1[C:10]([OH:9])=[C:11]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:12]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[C:13]=1[C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
HBr (33% in AcOH, 970 μL, 5.34 mmol) was added to a stirred solution of ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (6) (2.82 g, 5.34 mmol) in AcOH (40 mL) and the reaction was allowed to stir for 16 h at RT. The reaction mixture was diluted with DCM (100 mL), washed with water (100 mL), brine (2×100 mL), the organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was redissolved in AcOH (40 mL) and HBr (33% in AcOH, 970 μL, 5.34 mmol) was added dropwise and the reaction was allowed to stir at RT for 40 h. The reaction mixture was diluted with DCM (100 mL), washed with water (100 mL) and brine (2×100 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g, 0-30% EtOAc in toluene) to afford ethyl 4-(benzyloxy)-5-(dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (60) (1.48 g, 57%) as a colourless oil: m/z 439 (M+H)+ (ES+); 437 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.75 (s, 1H), 7.42-7.28 (m, 5H), 7.12-7.05 (m, 2H), 6.91-6.84 (m, 2H), 5.01 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 2.68 (s, 3H), 2.66 (s, 3H), 1.0 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17](NCCO)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)[CH:7]=[CH:6][C:5]=12.[CH3:24][N:25]([CH3:31])[C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([N:28]5[CH2:29][CH2:30][C@@H:26]([N:25]([CH3:31])[CH3:24])[CH2:27]5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CN(C)[C@@H]1CCNC1
Reactant: OCCNc1ccc2ncc(Cc3ccc4nccn4c3)n2n1
Product: CN(C)[C@@H]1CCN(c2ccc3ncc(Cc4ccc5nccn5c4)n3n2)C1

Procedure:
The title compound was prepared in analogy to the compound of Example 75 using dimethyl(R)-pyrrolidin-3-yl-amine as starting material (tR 0.93 min (conditions 7), MH+=362.1, 1H-NMR in DMSO-d6: 8.48 (s, 1H); 7.86 (s, 1H); 7.76 (d, 1H); 7.52 (s, 1H); 7.46 (d, 1H); 7.37 (s, 1H); 7.19 (d, 1H); 6.78 (d, 1H); 4.17 (s, 2H); 3.63 (m, 2H); 3.35 (m, 1H); 3.16 (m, 1H); 2.78 (m, 1H); 2.18 (m, 7H); 1.81 (m, 1H)).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C(O[K])(C)(C)C.[CH3:18][O:19][C:20]1[C:25]([CH2:26][O:27][CH2:28][O:29][CH3:30])=[C:24]([C:31](=O)[CH2:32][CH3:33])[CH:23]=[C:22]([Si:35]([CH3:38])([CH3:37])[CH3:36])[N:21]=1.[Na+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[C:31](/[C:24]1[CH:23]=[C:22]([Si:35]([CH3:36])([CH3:37])[CH3:38])[N:21]=[C:20]([O:19][CH3:18])[C:25]=1[CH2:26][O:27][CH2:28][O:29][CH3:30])\[CH2:32][CH3:33]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CCC(=O)c1cc([Si](C)(C)C)nc(OC)c1COCOC
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C(=C\C(=O)OC)c1cc([Si](C)(C)C)nc(OC)c1COCOC

Procedure:
To a mixture of trimethyl phosphonoacetate (2.5 mL, 15.3 mmol) and tBuOK (1.7 g, 15.3 mmol) in THF (20 mL) at 0° C. (1 h) was added a THF (10 nmL) solution of 18 (1.2 g, 3.7 mmol). The mixture was stirred at reflux for 36 h. Purification of the crude residue by flash chromatography (hexane/EtOAc 92:8) followed by preparative HPLC (hexane/EtOAc 92:8, Novapak normal phase cartridge column, 10 mL/min), afforded in order of elution; 18 (123.3 mg, 10%), 19E (387.0 mg, 27%) and 19Z (609.3 mg, 43%) as clear oils: 19E; 1H NMR (300 MHz, CDCl3) δ0.28 (s, 9H), 0.99 (t, J=7.6 Hz, 3H), 2.99 (q, J=7.6 Hz, 2H), 3.42 (s, 3H), 3.75 (s, 3H), 4.02 (s, 3H), 4.47 (s, 2H), 4.72 (s, 2H), 5.8 (s, 1H), 6.84 (s, 1H); 13C NMR (75 MHz, CDCl3) δ−2.0, 12.3, 14.2, 26.6, 51.2, 53.4, 55.3, 61.9, 96.7, 115.4, 118.9, 121.1, 150.9, 160.3, 162.2, 164.9, 166.2; IR (film, NaCl, cm−1) 2949, 1723, 1341, 1042, 840; LRMS (70 eV, EI) m/z (rel int %) 367 (M+), 352, 322, 308 (100), 290, 276, 246, 232, 99, 57; HRMS m/z calcd for C18H29NO5Si (M+) 367.1815,m found 367.1802. 19Z: 1H NMR (300 MHz, CDCl3) δ0.26 (s, 9H), 1.11 (t, J=7.2 Hz, 3H), 2.38-2.48 (m, 2H), 3.4 (s, 3H), 3.53 (s, 3H), 3.99 (s, 3H), 4.35 (d, J=10.2 Hz, 1H), 4.51 (d, J=10.2 Hz, 1H), 4.66 (dd, J=6.3 and 14.2 Hz, 2H), 5.94 (s, 1H), 6.72 (s, 1H); 13C NMR (75 MHz, CDCl3 δ−1.9, 11.4, 33.1, 51.1, 53.2, 55.2, 61.9, 96.5, 114.5, 116.3, 120.6, 150.0, 159.0, 161.7, 164.3, 165.6; IR (film, NaCl, cm−1) 2941, 1732, 1559, 1457, 1342, 1054, 836; LRMS (70 eV, EI) m/z (rel int %) 367 (M+), 322, 290, 278, 262, 139 (100), 89, 73; HRMS m/z calcd for C18H29NO5Si (M+) 367.1815, found 367.1820.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[NH:31]1[CH:35]=[C:34]([CH:36]=[O:37])[CH:33]=[N:32]1>C(#N)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([CH2:2][N:31]4[CH:35]=[C:34]([CH:36]=[O:37])[CH:33]=[N:32]4)=[CH:4][CH:5]=3)[N:10]=[C:9]([C:13]#[N:14])[CH:8]=2)=[CH:16][CH:17]=1
Reactant: O=Cc1cn[nH]c1
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C=O)cn3)cc2n1
Yield: 52.7 %

Procedure:
7-(Bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 100.0 mg, 0.293 mmol, 1.0 equiv.), DIEA (0.051 ml, 0.293 mmol, 1.0 equiv.), and 1-H-pyrazole-4-carbaldehyde (33.8 mg, 0.352 mmol, 1.2 equiv.) were added to acetonitrile (1.0 mL) in a microwave reaction vessel and the resulting mixture was irradiated with microwave at 180° C. for 30 minutes. The reaction mixture was cooled and concentrated and the residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(4-fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carbonitrile (3-8, 55.0 mg, 52.7%) as a colorless solid. LRMS m/z (M+H)+ 357.1 found, 357.1 required.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([O-:12])(=[O:11])=[S:10].[K+]>C(O)C.CCCCCC>[CH2:1]([O:12][S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[S:10])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Reactant: ClCc1ccccc1
Agent: [K+]
Solvent: CCCCCC
Solvent: CCO
Product: Cc1ccc(S(=O)(=S)OCc2ccccc2)cc1
Yield: 77.6 %

Procedure:
The title compound was prepared as described in General Method 2 using 0.05 mol of benzyl chloride, 0.05 moles of potassium thiotosylate in 150 mL of ethanol. The residue was dissolved in hexane and seeded with a crystal of the product to afford 10.8 g (77%) of benzyl-p-toluenethiosulfonate (m.p. 52-56.5° C.). 1H NMR (CDCl3) δ 2.45 (s, 3 H), 4.26 (s, 2 H), 7.18-7.30 (m, 7 H), 7.74 (d, 2 H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4](I)[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Oc1ccc(I)nc1Br
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: COCCOC
Solvent: O
Product: Oc1ccc(-c2ccc(Cl)cc2)nc1Br
Temperature: 80 °C
Yield: 51.7 %

Procedure:
A mixture of 2-bromo-6-iodopyridin-3-ol (0.65 g, 2.167 mmol), 4-chlorobenzeneboronic acid (339 mg, 2.167 mmol) and potassium carbonate (749 mg, 5.419 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (125.2 mg, 0.108 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 15 hours. The cooled reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous ammonium chloride solution (50 mL), the organic phase separated, washed with water (50 mL) and saturated brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 40% ethyl acetate in hexanes to give 2-bromo-6-(4-chlorophenyl)pyridin-3-ol (0.319 g, 52% yield) as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34]CC)=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([O:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 80 °C

Procedure:
A solution of ethyl 2-propoxy-1-[[2′-(1 H-tetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.23 g) in ethanol (4 ml) containing 1N-NaOH (1.5 ml) was heated at 80° C. for 2 Hours. The reaction mixture was concentrated to dryness and the residue was extracted with water and ethyl acetate. The aqueous layer was adjusted to pH 3-4 with 1N-HCl to give crystals. Recrystallization from ethyl acetate-methanol afforded colorless crystals (0.15 g, 69%), m.p. 174-175° C.
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[S:7])[CH:2]=1.[CH:13]1([CH2:19]N)[CH2:18][CH2:17][CH2:16]CC1>C(Cl)(Cl)Cl>[CH:10]1([CH2:9][NH:8][C:6]([NH:3][CH2:2][CH:1]2[CH2:16][CH2:17][CH2:18][CH2:13][CH2:19]2)=[S:7])[CH2:19][CH2:13][CH2:18][CH2:17][CH2:16]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NCC1CCCCC1
Solvent: ClC(Cl)Cl
Product: S=C(NCC1CCCCC1)NCC1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 720.9 %

Procedure:
A solution of N,N'-thiocarbonyldiimidazole (Aldrich, 90%, 3.64 g, 18.4 mmol) in chloroform (20 mL) was added dropwise to a solution of cyclohexanemethylamine (Aldrich, 98%, 5.00 g, 4.33 mmol) in chloroform (10 mL). The reaction mixture was then stirred at 50° C. for 2 h, cooled to ambient temperature, and washed with hydrochloric acid (0.1N, 3×50 mL) and water (50 mL). The organic layer was dried (magnesium sulfate), and concentrated under vacuum to a yellow solid, which was recrystallized from ethanol. The mother liquor from this crystallization was concentrated, and the resulting solid was recrystallized from toluene. The two crops of crystals were combined and dried under vacuum to provide 1,3-bis(cyclohexylmethyl)thiourea as a pale yellow powder (4.19 g, 85%), m.p. 124°-125° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:26][CH2:27][CH3:28])[C:5]2[S:25][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCOCC1>[CH2:27]([O:26][C:4]1[C:5]2[S:25][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=4)[N:12]=[C:13]([CH3:14])[C:8]=3[C:6]=2[N:7]=[C:2]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:3]=1)[CH3:28]
Reactant: CCOc1nc(Cl)nc2c1sc1nc(-c3ccc(OC(C)C)cc3)nc(C)c12
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(OC(C)C)cc3)nc(C)c12

Procedure:
0.1 g (0.24 mmol) 2-chloro-4-ethoxy-9-methyl-7-(4-iso-propoxy-phenyl)-thieno[2,3-d:4,5-d′]dipyrimidine and 83 mg (0.96 mmol) piperazine are refluxed in 40 ml dioxane for 4 h. Thereafter, the solvent is removed and the residue is suspended in water and sucked off. Following flash chromatography (chloroform/ethanol 10:2) 20 mg (18%) of the title substance is obtained.