Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[C:9](O)(=O)[C:10](C)([CH3:12])[CH3:11].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[NH4+].[OH-]>OS(O)(=O)=O.O.[N+]([O-])([O-])=O.[Ag+]>[C:10]([C:6]1[CH:5]=[CH:4][C:3]([CH:7]=[O:8])=[CH:2][N:1]=1)([CH3:12])([CH3:11])[CH3:9]
Reactant: CC(C)(C)C(=O)O
Reactant: OCc1cccnc1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CC(C)(C)c1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
3-Pyridinemethanol (2.2 g, 20.2 mmol), pivalic acid (10.3 g, 100.8 mmol) and silver nitrate (0.68, 4.0 mmol) were suspended in 10% aqueous H2SO4 (20 ml). Ammonium persulfate (9.2 g, 40.3 mmol) in H2O (40 ml) was added to the mixture. The mixture was stirred at r.t. for 2.0 h. NH4OH was added until pH=9. The product was extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (Pet. Ether/EtOAc 70:30) to give the title substance in 43% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3C(O)[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[C:27]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)(N1C=CN=C1)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[CH:27]([N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3n2ccnc2)cc1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
A solution of methyl[4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetate (Compound 135, 140.0 mg, 0.40 mmol) and carbonyldiimidazole (136.0 mg, 0.84 mmol) in 5 mL THF was heated to 65° C. for 48 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in Et2O and washed with 5% aqueous NaOH, H2O, and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (5% MeOH—CH2Cl2) afforded 50.0 mg (31%) of the title compound as a colorless solid.
Reaction SMILES: [CH:1]1([N:4]2[CH:10]([CH3:11])[CH:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:5]2=3)[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:64][CH:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:4]2[CH:10]([CH3:11])[CH:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([NH:64][CH:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:26])=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:5]2=3)[CH2:2][CH2:3]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CC1)C(C)C(C)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CC1)C(C)C(C)C(=O)N2C
Reaction time: 0.08 h
Yield: 73.9 %

Procedure:
A mixture of 0.082 g (0.0002 mole) of (rac)-4-(9-cyclopropyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-46a), 0.091 g (0.00024 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 mL (0.0003 mole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.034 g (0.0003 mole) of 4-amino-1-methyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.075 g of (rac)-4-(9-cyclopropyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-46) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[NH:13][C:12]([C:19]([O:21]C)=[O:20])=[CH:11]2.[OH-].[Na+]>CC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[NH:13][C:12]([C:19]([OH:21])=[O:20])=[CH:11]2
Reactant: COC(=O)c1cc2cc(OCc3cc(OC)c(OC)c(OC)c3)c(OC)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: COc1cc2[nH]c(C(=O)O)cc2cc1OCc1cc(OC)c(OC)c(OC)c1

Procedure:
180 mg of methyl 5-(3,4,5-trimethoxybenzyloxy)-6-methoxy-1H-indole-2-carboxylate are dissolved in 15 ml of acetone and 3 ml of methanol. 15 ml of 1N sodium hydroxide are added and the mixture is left to react for 2 hours at 30° C. The solvents are evaporated off under vacuum and the residual aqueous phase is acidified to pH 2 with concentrated hydrochloric acid. A solid is obtained, which is purified by taking it up in ethyl acetate at room temperature.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](=[NH:14])OCC.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].OS(O)(=O)=O>CO>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:15][NH:16][C:17]([NH2:19])=[S:18])=[NH:14]
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1C
Reactant: NNC(N)=S
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S

Procedure:
To a stirred mixture of ethyl 1-methyl-5-nitro-2-imidazolecarboximidate (0.198 g., 0.001 mole) and thiosemicarbazide (0.091 g., 0.001 mole) in 5 ml. of methanol is added 1 drop of cone. H2SO4 and the mixture is stirred at room temperature for 50 minutes. The solid is filtered and washed with methanol, yielding 0.149 g. of the title compound, melting point 200°-201°C. dec.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[N:23][NH2:24])[C@H:19]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:18][CH2:17]1.[F:33][C:34]([F:40])([F:39])[CH2:35][C:36](O)=O.ON1C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:36]([CH2:35][C:34]([F:40])([F:39])[F:33])=[N:24][N:23]=[C:20]2[C@H:19]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=NN
Reactant: O=C(O)CC(F)(F)F
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Reaction time: 18 h
Yield: 89.3 %

Procedure:
Triethylamine (0.259 mL, 1.86 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-hydrazonoazepan-3-ylcarbamate (548 mg, 1.55 mmol), 3,3,3-trifluoropropionic acid (0.205 mL, 2.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimmide hydrochloride (356 mg, 1.86 mmol), and 1-hydroxy-7-azabenzotriazole (253 mg, 1.86 mmol) in dichloromethane (55 mL). After 18 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→96% dichloromethane/methanol) gave the title compound (618 mg). MS 447.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[O:14][C:15]([CH3:19])=[CH:16][C:17]=1[SH:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:12][C:13]1[O:14][C:15]([CH3:19])=[CH:16][C:17]=1[S:18][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(S)c(C)o1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2cc(C)oc2C)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 113.6 %

Procedure:
The title compound was prepared from 1-Chloro-4-methyl-2-nitro-benzene (2.00 g, 11.7 mmol), 2,5-Dimethyl-furan-3-thiol (1.50 g, 11.7 mmol), and K2CO3 (3.233 g, 23.4 mmol) heated in DMF at 100° C. for 4 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (3.5 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[C:5]([Cl:30])=[CH:4][N:3]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O.C(O)(=O)C>ClCCl>[Cl:30][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)=[CH:7][C:2]([NH:1][CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)=[N:3][CH:4]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cc(N)ncc4Cl)ccnc3[nH]2)CC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cc(NCc5cccc(F)c5)ncc4Cl)ccnc3[nH]2)CC1
Reaction time: 8 h

Procedure:
To a solution of Example 307A (74 mg, 0.17 mmol) and 3-fluorobenzaldehyde (107 mg, 0.86 mmol) in dichloromethane was added acetic acid (0.05 mL, 0.86 mmol) and MP-CNBH3 (2.49 mmol/g) (278 mg, 0.69 mmol). The mixture was stirred overnight and the insoluble material was filtered off. The filtrated was concentrated. The residue was purified by flash chromatograph eluting with a gradient of 10%-50% ethyl acetate in hexanes to provide the title compound. LCMS: 537 (M+H)+.
Reaction SMILES: CC(O[C:5]1[C:9](=[O:10])[C:7](=[O:8])[C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])C.[Sn:15]([Si](C)(C)C)([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH3:14][CH:12]([O:11][C:6]1[C:7](=[O:8])[C:9](=[O:10])[C:5]=1[Sn:15]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13]
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 0.052M n-Bu4N+CN- in tetrahydrofuran (7.69 mL, 0.4 mmol) was added dropwise to a stirred solution at -20° C. of diisopropyl squarate (3.96 g, 0.020 mol) and n-Bu3SnSi(CH3)3 (7.27 g, 0.020 mol) in tetrahydrofuran (154 mL). Stirring was continued at -20° C. for 2 hrs. The solution was concentrated and the residue chromatographed on SiO2 with diethyl etherhexane (10:90) to afford the title compound (5.75 g, 67% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]([OH:17])=O.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:23]1([NH:22][C:15](=[O:17])[CH2:14][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=3)[S:6][C:2]=2[Br:1])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1Br
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C(Cc1nc(-c2ccc(Cl)cc2)sc1Br)Nc1ccccc1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
A mixture of 5-bromo-2-(4-chlorophenyl)thiazol-4-yl-acetic acid (1 g, 3 mmol), thionyl chloride (2 equiv., 0.72 g, 6 mmol), and chloroform were heated under reflux for 2.5 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was dissolved in CHCl3 (dry), followed by dropwise addition of aniline (2 equiv., 0.56 g, 6 mmol) and the resulting mixture refluxed for a further 5 hours. The reaction mixture cooled to room temperature and the precipitate was collected by filtration. The filtrate was concentrated under reduced pressure. The residue was triturated with EtOAc, and filtered to yield the desired product (0.4 g, 32%).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[C:20][CH2:21][CH3:22])[CH:12]=O.C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:26]/[C:27]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[C:20][CH2:21][CH3:22]
Reactant: CCC#CCOc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCC#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 59.9 %

Procedure:
Piperidine (0.22 mL, 2.2 mmol) was added to a suspension of 3-methoxy-4-(pent-2-ynyl)oxybenzaldehyde (0.50 g, 2.3 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.49 g, 2.2 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-[[3-(3-Methoxy-4-(pent-2-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.50 g, 60%) was obtained as a colourless crystalline solid; mp 185.5-186.5° C.; δH (400 MHz, DMSO-d6) 1.05 (t, J=7.4 Hz, 2H, CH2CH3), 2.20 (q, J=7.4 Hz, 3H, CH2CH3), 3.84 (s, 3H, OCH3), 4.78 (s, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 7.03 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5 8.0 Hz, 1H, H4), 7.24 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.39 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.53 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 11.7, 13.5, 56.6, 56.4, 74.7, 89.3, 110.7, 113.3, 116.6, 120.2, 120.3, 122.2, 122.7, 127.9, 131.1, 134.0, 141.0, 141.5, 148.5, 149.2, 164.1, 169.5; HRMS (ESI) calculated for C22H21NO6 [M+Na]+ 402.1312. found 402.1317; vmax 747, 1001, 1253, 1508, 1583, 1661, 2980, 3246, 3523 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].C([O-])=O.[NH4+]>CCOC(C)=O.CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccncn2)c1Cl)c1c(F)cccc1F
Temperature: 60 °C
Yield: 31.5 %

Procedure:
To a solution of N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.26 mmol) and ammonium formate (0.16 g, 2.6 mmol) in EtOAc (7 mL) and MeOH (7 mL) was added 20% palladium hydroxide on carbon (0.16 g, 0.23 mmol). The reaction mixture was heated to 60° C. for 2 h. The palladium was filtered off using a nylon membrane. The filtrate was concentrated under vacuum to a crude yellow solid. The residue was purified by silica gel chromatography eluting 10-100% EtOAc/hexanes to afford the title compound as a bright yellow solid (0.045 g; 29.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1H), 8.96 (d, J=1.3 Hz, 1H), 8.36 (d, J=5.6 Hz, 1H), 7.62-7.75 (m, 1H), 7.44-7.55 (m, 2H), 7.38 (d, J=6.1 Hz, 1H), 7.22 (t, J=9.1 Hz, 2H), 6.25 (dd, J=5.6, 1.3 Hz, 1H), 3.66-3.76 (m, 4H), 3.46-3.54 (m, 4H). MS (ESI) 550.1 [M+H]+.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Si]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=O)=[CH:24][CH:23]=1>C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(O)cc1)c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
A solution of lithium hexamethyldisilazide (23.1 mL, 1 M in THF) was added to a stirred solution of ethyl (trimethylsilyl)acetate (2.53 mL, 13.9 mmol) in THF (15 mL) in 10 minutes at −78° C. The reaction mixture was further stirred at this temperature for 20 minutes. A solution of (4-fluoro-phenyl)-(4-hydroxy-phenyl)-methanone (2 g, 9.2 mmol) in THF (30 mL) was slowly added to the reaction mixture. The reaction mixture was brought to 0° C. over 5 hours. The reaction mixture was quenched with saturated NH4Cl solution, extracted into EtOAc and washed with dilute NH4Cl solution. The organic layer was dried over magnesium sulfate. The solvent was removed under vacuum, and the resulting product was flash chromatographed on silica gel, giving M2.1 as an oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][C:5]2=[N:4][CH:3]=1.C([Mg]Br)(C)C.I[C:16]1[N:28]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:19]2=[N:20][CH:21]=[C:22]3[CH:26]=[N:25][N:24]([CH3:27])[C:23]3=[C:18]2[CH:17]=1.O>C1COCC1.CN(C=O)C.[Cl-].[Zn+2].[Cl-].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>[N:4]1[CH:3]=[C:2]([C:16]2[N:28]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:19]3=[N:20][CH:21]=[C:22]4[CH:26]=[N:25][N:24]([CH3:27])[C:23]4=[C:18]3[CH:17]=2)[N:6]2[CH2:7][CH2:8][CH2:9][C:5]=12
Reactant: Brc1cnc2n1CCC2
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnc4n3CCC4)cc3c4c(cnc32)cnn4C)cc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 241.7 %

Procedure:
To a flask was added 3-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (0.250 g, 1.33 mmol, Apollo) and THF (3 mL). The mixture was cooled to about −30° C. and then i-PrMgBr (2.0 M in THF, 0.735 mL, 1.47 mmol) was added. After about 15 min, in a separate flask, zinc chloride (0.219 g, 1.604 mmol) was dissolved in THF (3 mL) and then the solution was added dropwise to the mixture. After about 30 min at about −20° C., 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.250 g, 0.553 mmol; Preparation #1) and Pd(Ph3P)4 (0.093 g, 0.080 mmol), dissolved in DMF (2 mL) were then added to the mixture and it was then heated to about 80° C. for about 90 min. Water was added (30 mL) and solids were collected by filtration and dried under reduced pressure to provide 7-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.578 g, 100%): LC/MS (Table 2, Method c) Rt=1.27 min; MS m/z 433 (M+H)+.
Reaction SMILES: [CH2:1]([CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:26]=[O:27].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>O>[C:18]([C:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])([CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:26][OH:27])#[N:19]
Reactant: N#CC(CCc1ccccc1)c1ccc(Cl)cc1Cl
Reactant: C=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: N#CC(CO)(CCc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an ice cold stirred solution of α-phenethyl-2,4-dichlorobenzyl cyanide (26.5g., 0.09 mole) in 200 ml. of pyridine containing a suspension of paraformaldehyde (11g., 0.35 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 24 hours. The reaction mixture is poured into 1 liter of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 25.4g. of a thick oil, which is identified by nmr.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]1([C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2ccc(-c3ccccc3)cn2)CC1
Yield: 15 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (235 mg, 0.872 mmol), 1-(5-phenylpyridin-2-yl)piperazine (200 mg, 0.872 mmol), diisopropylethylamine (0.3047 ml, 1.74 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, then the reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduce pressure, and the residue was recrystallized from ethyl acetate to give the titled compound 47 mg (47.0%) as solid product.