Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(S([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[C:18]([C:25]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[N:28][N:27]4[CH2:36][CH2:37][CH2:38][C:26]=34)=[CH:17]2)(=O)=O)C=CC=CC=1>CO.O>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]1[C:25]([C:18]2[C:19]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:16][CH:17]=2)=[C:26]2[CH2:38][CH2:37][CH2:36][N:27]2[N:28]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2c(-c3ccccn3)nn3c2CCC3)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: c1ccc(-c2nn3c(c2-c2c[nH]c4ncccc24)CCC3)nc1
Yield: 6.9 %

Procedure:
Add potassium carbonate (21 mg, 0.15 mmol) to a solution of 1-benzenesulfonyl-3-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (Example 3, Part A; 34 mg, 0.77 mmol) in methanol/water (0.9 mL/0.3 mL). Reflux the reaction overnight (16 h). Concentrate in vacuo, add aqueous sodium chloride (10 mL), and extract with chloroform (3×25 mL). Dry the combined organic extracts with sodium sulfate, filter, and concentrate in vacuo. Purify by flash column chromatography, using the appropriate mixture of methylene chloride, chloroform, methanol, and concentrated aqueous ammonium hydroxide, to provide 16 mg (68%) of the title compound as an off-white solid. MS (ES) m/z=302 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:40])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[S:31][C:32]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:9][CH:8]([CH3:10])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[S:31][C:32]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6]([OH:40])=[O:5]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4cc(Cl)ccc4s3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4cc(Cl)ccc4s3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 386.1 %

Procedure:
To (S)-3-methyl-2-{4′-[(5-chloro-benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester (30 mg) was added 3 mL of TFA/CH2Cl2 (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 105 mg of (S)-3-methyl-2-{4′-[(5-chloro-benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.88 (m, 6 H) 1.85-2.07 (m, 1 H) 3.56 (dd, 1 H) 7.70 (dd, 1 H) 7.76-7.94 (m, 6 H) 8.03-8.12 (m, 3 H) 8.26 (d, 1 H) 8.35 (d, 1 H) 11.36-11.40 (m, 1 H).
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([OH:33])[CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH3:32]>C(Cl)Cl>[CH3:8][S:9]([O:33][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH3:32])(=[O:11])=[O:10]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Et3N (1.50 mL, 10.8 mmol) and methanesulfonyl chloride (402 μL, 5.20 mmol) was added to a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-ol (1.15 g, 4.0 mmol) in CH2Cl2 (40 mL) held at 0° C. under nitrogen. The mixture was stirred at 0° C. for one hour, and poured into ice-water (100 g) and the water phase extracted with Et2O (50 mL). The combined organic extracts were added 0.5 M H2SO4 (35 mL), the organic phase washed with NaHCO3 (sat. aq.) (25 mL), before dried (Mg2SO4, gram). Filtration and concentration in vacuo afforded 1.24 gram of crude oil. Purification on Armen, SVP D26 column packed with 30 gram of 15-40 μm Merck silica, flow 20 mL/min, UV 210 nm and collecting 15 mL fraction, was performed using gradient elution: (starting heptane:EtOAc (100:0) and increasing during 10 min. to 10% EtOAc, then increasing 5 min. to 20% EtOAc (hold 10 min.), then increasing in 5 min. to 40% EtOAc (hold 0 min.). Fractions 6-14 afforded 1.16 g (79% yield) of the title compound as oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:17]I>O1CCCC1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([CH3:17])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 39.4 %

Procedure:
At first, 4.2 g of 60% sodium hydride was suspended in 200 ml of tetrahydrofuran, and then a solution of 18.9 g of 1-benzyl-4-piperidone and 17.9 g of methyl iodide dissolved in 20 ml of tetrahydrofuran was added dropwise to the suspension at room temperature over 5 minutes. Thereafter, the mixture was heated to 60° C. and stirred for 5 hours. Thereafter, the reaction mixture was filtered. The filtrate was concentrated, and then the concentrate was poured into 150 ml of water and extracted with 120 ml portions of ethyl acetate three times. The extract was washed with 150 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 21.6 g of an oily matter. The oily matter was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=2:1 V/V) to obtain 8.0 g of 1-benzyl-3-methyl-4-piperidone.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[N+:18]([O-])=O)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[Si:5]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[NH2:18])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7]
Reactant: COc1ccc([N+](=O)[O-])c(CO[Si](C)(C)C(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
To a solution of tert-butyl(5-methoxy-2-nitrobenzyloxy)dimethylsilane (14.0 g, 47.1 mmol) in EtOH (200 mL) was added 10% Pd/C (1.40 g), the mixture was stirred at 30° C. for 2 hours under H2 (40 psi). The solids were filtered off and the filtrate was concentrated under reduced pressure to give the product (14.0 g) as a yellow oil. 1H NMR (DMSO 400 MHz): δ 6.75 (d, J=2.4 Hz, 1H), 6.60-6.55 (m, 2H), 4.55 (s, 2H), 4.40 (brs, 2H), 3.61 (s, 3H), 0.90 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(O)C>[C:15]([O:14][C:12](=[O:13])[CH2:11][NH:4][CH:1]1[CH2:3][CH2:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC1CC1
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Cyclopropylamine (19.5 g, 0.342 mol) was placed in a pressure bottle and ethanol (100 ml.) was added. The resulting solution was cooled in an ice bath and sodium bicarbonate (8.5 g, 0.101 mol) and t-butyl bromoacetate (15.5 g, 0.0795 mol) was added. The flask was stoppered and the contents of the flask were stirred for 30 minutes with external cooling (ice bath) and then at room temperature overnight. Most of the solvent was removed on a rotary evaporator and water was added to the residue. The product was extracted several times with chloroform. The combined chloroform extract was washed with water, dried over sodium sulfate, filtered and evaporated to yield the product as a pale yellow oil (12.5 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([OH:9])[C:3]=1[OH:10].[C:11](Cl)(Cl)=[S:12].[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]2[O:10][C:11](=[S:12])[O:9][C:4]=2[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Oc1c(F)ccc(Br)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Fc1ccc(Br)c2oc(=S)oc12
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
3-Bromo-6-fluorobenzene-1,2-diol (8.9 g, 43 mmol) was dissolved in chloroform (100 mL), cooled to 0-5° C. and treated with thiophosgene (5.4 g, 47 mmol). Aqueous sodium hydroxide solution (10 wt %; 40 g, 99 mmol) was added in portions over 30 min with vigorous stirring. Stirring was continued for 60 min at 5-15° C. and then most of the chloroform was removed by rotary evaporation. The pH was adjusted to 2 by addition of 1 M HCl and the precipitated thione was taken up in ethyl acetate (150 mL). The organic phase was washed with water (25 mL), saturated NaCl (25 mL), dried (Na2SO4), and evaporated. The crude product was purified by flash chromatography, eluting with a 0-20% ethyl acetate-hexane gradient to give the title compound as a tan solid (6.2 g, 58%): mp 72-76° C.; 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J=9.2, 4.1 Hz, 1H), 7.04 (t, J=9.1 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −132.68; EIMS m/z 248.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.Cl.[C@H:10]1([NH2:18])[C:12]2([CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.CCOC(C)=O>[Br:8][C:4]1[N:3]=[C:2]([NH:18][C@H:10]2[C:12]3([CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H]1CC12CCOCC2
Reactant: Brc1cccc(Br)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Brc1cccc(N[C@@H]2CC23CCOCC3)n1
Temperature: 110 °C
Yield: 88.3 %

Procedure:
To a solution of 2,6-dibromopyridine (200 mg, 0.84 mmol) in NMP (0.42 mL) was added (R)-6-oxaspiro[2.5]octan-1-amine hydrochloride (138 mg, 0.84 mmol) and potassium carbonate (350 mg, 2.53 mmol). The mixture was heated at 110° C. for 18 hr. The mixture was allowed to cool to ambient temperature and diluted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water, and brine and dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane= 0/100 to 30/70]. Pure fractions were combined and concentrated in vacuo giving 210 mg of titled compound. LCMS (m/z): 282.9/284.9 [M+H]+, retention time=0.85 min.
Reaction SMILES: COC([N:5]1[CH2:10][CH:9]([CH2:11][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:13][CH3:14])[C:8](=[O:24])N(C)C1C(C)(C)C)=O.Cl.[O:31]1CCOCC1>>[NH2:5][CH2:10][C@@H:9]([CH2:11][C@H:12]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])[CH2:13][CH3:14])[C:8]([OH:24])=[O:31]
Reactant: CCC(Cc1ccc(F)cc1F)CC1CN(C(=O)OC)C(C(C)(C)C)N(C)C1=O
Reactant: C1COCCO1
Agent: Cl
Product: CC[C@@H](Cc1ccc(F)cc1F)C[C@H](CN)C(=O)O
Temperature: 110 °C
Yield: 24 %

Procedure:
A flask was charged with 0.5 g (1.2 mmol) of 2-tert-butyl-5-[2-(2,4-difluoro-benzyl)-butyl]-3-methyl-4-oxo-tetrahydro-pyrimidine-1-carboxylic acid methyl ester, 20 mL of dioxane, and 20 mL of conc. HCl solution. The mixture was stirred and heated at 110° C. for 4 days. The solvents were removed under reduced pressure. The residue was taken up in 20 mL of water and 4 drops of conc. HCl solution. The aqueous layer was washed with dichloromethane. The aqueous layer was collected and the water was removed under reduced pressure. The residue was treated with 2 mL of triethylamine, and the excess triethylamine was removed under reduced pressure. The remaining solid was purified by column chromatography (1:8:27 NH4OH, MeOH, dichloromethane eluent). The resulting white solid was washed with acetonitrile and dried under vacuum. This gave 80 mg (24% yield) of the titled compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.Cl.[F:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:38]3[CH2:39][CH2:40][C@H:36]([F:35])[CH2:37]3)[CH:3]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(Br)c1)C2
Reactant: F[C@H]1CCNC1
Agent: Cl
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(N3CC[C@H](F)C3)c1)C2

Procedure:
The title compound was prepared by the method of Preparation 12c using (R)-6-(5-bromopyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and (S)-3-fluoropyrrolidine hydrochloride. LCMS (Method F): 542 (M+H)+, Retention time 4.9 minutes.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:13]1([S:19]([N:1]2[C:9]3[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=3[CH:3]=[CH:2]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A stirred solution of 1,5,6,7-tetrahydro-4H-indol-4-one (5.0 g, 37.0 mmol) in THF is treated portionwise with NaH (60% dispersion in mineral oil, 1.5 g, 37.0 mmol) under N2 at room temperature, stirred for 0.5 hr, treated with benzene sulfonyl chloride (4.7 ml, 37.0 mmol), stirred for 24 hr, quenched with water and diluted with EtOAc. The phases are separated. The organic phase is washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexanes, 1/1 as eluent) to afford the title product as an off-white solid, 8.72 g (85% yield), mp 108-110° C., identified by NMR and mass spectral analyses.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)N=CC)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:25][C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=O.O>C(O)(=O)C>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]3[C:17]4[C:22](=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:26]3[CH3:25])=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CC=NN(c1ccc(OC)cc1)c1ncnc2cc(Cl)ccc12
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1ncnc2cc(Cl)ccc12

Procedure:
A mixture of acetaldehyde N1 -(7chloroquinazolin-4-yl)-p-methoxyphenylhydrazone hydrochloride (25g.) and laevulinic acid (50g.) in acetic acid (120ml.) was heated under reflux for 1-2 hours. The dark red mixture was then added to water (1.5 1.). The solid obtained was separated by filtration and dissolved in a mixture of water (50ml.) and 5N-aqueous ammonium hydroxide solution (50ml.). The solution was extracted with ether (3 × 50ml.) and the aqueous layer acidified with acetic acid to pH4. The mixture was then extracted with ethyl acetate (3 × 50ml.) and the extracts washed with water (30ml.) and then with saturated sodium chloride solution (30ml.) before being dried (MgSO4). Evaporation of the solvent gave a dark brown syrup which crystallised on addition of methanol (40ml.) to give 1-(7-chloroquinazolin-4-yl)5-methoxy-2-methylindol-3-ylacetic acid as a yellow solid, m.p. 205°-208° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:17][C:18]([OH:20])=O)[C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[S:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:18](=[O:20])[CH2:17][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Solvent: O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2Sc2ccccc21

Procedure:
78.4 g of 3-nitro-6-(phenylthio)-phenylacetic acid and 400 g of polyphosphoric acid are held at 105° - 110° C for 90 minutes with stirring. The mixture is subsequently diluted with ice and water and extracted with benzene. The organic phase is washed successively with water and aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated under reduced pressure. There is obtained 10,11 -dihydro- 2-nitro-dibenzo[b,f]thiepin-10-one of melting point 171° - 172° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]3[N:19]([CH3:20])[C:18]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[N:17][N:16]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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>[O:26]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([C:8]3[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]4[N:19]([CH3:20])[C:18]([C:21]5[S:22][CH:23]=[CH:24][CH:25]=5)=[N:17][N:16]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:27]1
Reactant: OB(O)c1ccoc1
Reactant: Cn1c(SCc2noc(-c3cccc(I)c3)n2)nnc1-c1cccs1
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: CCOC(C)=O
Solvent: COCCOC
Product: Cn1c(SCc2noc(-c3cccc(-c4ccoc4)c3)n2)nnc1-c1cccs1
Temperature: 90 °C
Yield: 59.3 %

Procedure:
To 5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole (50 mg, 0.10 mmol) in a vial was added 3-furan boronic acid (17 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.0052 mmol), ethylene glycol dimethyl ether (1 ml) and 2 M sodium carbonate (1 ml). The vial was then sealed and heated at 90° C. for 1 h with vigorous stirring. The reaction was cooled, diluted with ethyl acetate, washed with water and saturated brine, filtered and concentrated. The residue was purified by flash column chromatography using 70% ethyl acetate in hexanes. Additional purification by trituration with a mixture of diethyl ether and hexanes and then filtration afforded the title compound as a beige solid 25 mg (57%). 1H NMR (CDCl3), δ (ppm): 8.18 (s, 1H), 7.98 (d, 1H), 7.79 (s, 1H), 7.71 (d, 1H), 7.51 (m, 4H), 7.17 (m, 1H), 6.74 (s, 1H), 4.55 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[N:11]([C:32]2[S:33][C:34]([CH3:37])=[N:35][N:36]=2)[N:10]=1.Cl.CCOCC>CCOCC.C(Cl)Cl>[NH2:24][CH2:23][CH2:22][CH2:21][C:12]1([C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[N:11]([C:32]2[S:33][C:34]([CH3:37])=[N:35][N:36]=2)[N:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:13]1
Reactant: Cc1nnc(N2N=C(c3cc(F)ccc3F)SC2(CCCNC(=O)OC(C)(C)C)c2cccc(O)c2)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nnc(N2N=C(c3cc(F)ccc3F)SC2(CCCN)c2cccc(O)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
Tert-butyl 3-(5-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (51 mg, 0.093 mmol) was weighed into a 25 mL flask, and dissolved in 7 mL of Et2O/DCM (1:1). HCl-Et2O (1.8 mL, 1.863 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. An additional 20 equivalents of HCl-Et2O was added and the reaction mixture was stirred an additional 2 hours. The crude reaction mixture was concentrated in vacuo to afford a yellow solid. The solid was then purified by flash column chromatography (10-40% MeOH/DCM), affording the desired product (31 mg, 74% yield) as a yellow foam. MS ESI (+) m/z 448 (M+1) detected; 1H NMR (400 MHz, DMSO-D6) δ 7.90 (m, 1H), 7.51 (m, 2H), 7.19 (m, 1H), 6.84 (m, 2H), 6.74 (m, 1H), 3.21 (m, 1H), 2.98 (m, 1H), 2.89 (m, 2H), 2.56 (m, 3H), 2.61 (m, 1H), 2.10 (m, 1H), 1.60 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:11](C(OC(C)(C)C)=O)[C:10]2[N:9]=[CH:8][C:7]([C:19]([F:22])([F:21])[F:20])=[CH:6][C:5]=2[CH2:4][NH:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:21][C:19]([F:20])([F:22])[C:7]1[CH:8]=[N:9][C:10]2[CH2:11][C:2](=[O:1])[NH:3][CH2:4][C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)C1C(=O)NCc2cc(C(F)(F)F)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Cc2ncc(C(F)(F)F)cc2CN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of tert-butyl 7-oxo-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxylate (3.60 g, 11.4 mmol) in methylene chloride (14 mL) was added trifluoroacetic Acid (6.75 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The solution was evaporated under reduced pressure and the residue was dissolved in CH2Cl2. The mixture was neutralized by the slow addition of a solution of saturated NaHCO3 and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 four times, and the combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo to afford 2.45 g (100%) of desired product as a yellow solid. LC-MS calculated for C9H7F3N2O: (M+H)+217; found 217.0.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[NH:7]1[C:3]([CH2:2][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][N:5]=[N:6]1
Reactant: ClCc1nnn[nH]1
Reactant: C1COCCN1
Product: C1CN(Cc2nnn[nH]2)CCO1
Yield: 80.6 %

Procedure:
A solution of 5-(chloromethyl)-1H-tetrazole (260 mg, 2.2 mmol) in morpholine (1.5 mL, 17.2 mmol) was stirred at 25° C. for 20 minutes. The crude reaction mixture was purified by preparative LCMS using pH 2 buffer to yield the desired product (300 mg, 82%). MF═C6H11N5O; LCMS calculated for C6H12N5O(M+H)+: m/z=170.1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=O)=[CH:6][N:5]=[C:4]2[NH:18][CH:19]=[CH:20][C:3]=12.[CH3:21][NH:22][NH2:23]>C(O)CCC>[CH3:21][N:22]1[C:2]2=[C:3]3[CH:20]=[CH:19][NH:18][C:4]3=[N:5][CH:6]=[C:7]2[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[N:23]1
Reactant: CNN
Reactant: CSc1ccc(C(=O)c2cnc3[nH]ccc3c2Cl)cc1
Solvent: CCCCO
Product: CSc1ccc(-c2nn(C)c3c2cnc2[nH]ccc23)cc1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
To (4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-(methylthio)phenyl)methanone (0.20 g, 0.66 mmol, prepared using S from 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde [Preparation #1, Step B] and AV) in BuOH (4 mL) was added methylhydrazine (0.052 mL, 0.991 mmol). The mixture was stirred for about 1.5 h at about 95° C. and then cooled to rt. The resulting precipitate was collected by filtration, washed with EtOAc (2 mL) and dried in a vacuum oven at about 70° C. for about 2 h to give 1-methyl-3-(4-(methylthio)phenyl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.15 g, 77%): LC/MS (Table 2, Method a) Rt=2.23 min.; MS m/z: 295 (M+H)+. Syk IC50=A.