Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4C4NN=NN=4)=[CH:15][CH:14]=3)=[CH:9][C:8]([CH2:30][CH3:31])=[N:7][C:6]=12.[C:32](C1C=CC=CC=1C1C=CC(CNC)=CC=1)#[N:33].[CH2:49](O)C>>[Cl:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:32]#[N:33])=[CH:17][CH:18]=3)[CH3:49])=[CH:9][C:8]([CH2:30][CH3:31])=[N:7][C:6]=12
Reactant: CCO
Reactant: CCc1cc(NCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n2ncc(Cl)c2n1
Reactant: CNCc1ccc(-c2ccccc2C#N)cc1
Product: CCc1cc(N(C)Cc2ccc(-c3ccccc3C#N)cc2)n2ncc(Cl)c2n1

Procedure:
3.1 g (14.4 mmol) of the chloro compound (Example 3, Step A) and 3.2 g (14.4 mmol) of the amine (Example 1, Step C) were heated in 75 ml ethanol according to Example 4, Step C. The title compound was obtained as an oil after chromatography (silica gel; dichloromethane with ascending polarity by addition of up to 3% ethanol).
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:5]=1[O:6][C:7]1[C:8]([NH2:20])=[N:9][C:10]([NH:13][CH:14]2[CH2:19][CH2:18]S[CH2:16][CH2:15]2)=[N:11][CH:12]=1)([CH3:3])[CH3:2].O[O:30][S:31]([O-:33])=O.[K+].[ClH:35].CCOCC>CO.O>[ClH:35].[O:30]=[S:31]1(=[O:33])[CH2:18][CH2:19][CH:14]([NH:13][C:10]2[N:9]=[C:8]([NH2:20])[C:7]([O:6][C:5]3[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:4]=3[CH:1]([CH3:3])[CH3:2])=[CH:12][N:11]=2)[CH2:15][CH2:16]1
Reactant: O=S([O-])OO
Reactant: COc1cc(Oc2cnc(NC3CCSCC3)nc2N)c(C(C)C)cc1OC
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COc1cc(Oc2cnc(NC3CCS(=O)(=O)CC3)nc2N)c(C(C)C)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-isopropyl-4,5-dimethoxy-phenoxy)-N*2*-(tetrahydro-thiopyran-4-yl)-pyrimidine-2,4-diamine (0.19 g, 0.46 mmol) in 25 mL of methanol and 25 mL of water was added the OXONE (1.73 g, 1.4 mmol). This mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The organic solution was washed with Brine, dried over MgSO4. The solution was filtered and concentrated. The residue was purified on one preparative TLC plate (20×40 cm) eluting with EtOAc. Product recovered was stirred with 1.5 eq of 1M HCl/ether to afford 25 mg of N*2*-(1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-5-(2-isopropyl-4,5-dimethoxy-phenoxy)-pyrimidine-2,4-diamine HCl salt): MS (M+H); 441: MP; 255.1-257.8° C.
Reaction SMILES: [C:1]1([P:7](=[O:17])([O-:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:1]1([P:7](=[O:16])([O:17][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCN1CCOCC1
Reactant: O=P([O-])(OCc1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=P(OCCN1CCOCC1)(OCc1ccccc1)c1ccccc1
Temperature: 65 °C
Reaction time: 22 h
Yield: 74.6 %

Procedure:
A mixture of monobenzyl phenylphosphonate (115 mg, 0.46 mmol), N-(2-chloroethyl)morpholine hydrochloride (95 mg, 0.51 mmol) and potassium carbonate (140 mg, 1.0 mmol) in anhydrous DMF was stirred at 65° C. for 22 hours. Following dilution with ethyl acetate (40 ml), the mixture was washed with water four times and finally brine before being dried over magnesium sulfate, filtered and concentrated to leave 124 mg (74%) of the title compound as a pale yellow oil which was used without further purification. MS: 362 m/z (M+H)+.
Reaction SMILES: C(C(CCCC)CO[C:6](=O)[CH2:7][CH2:8][S:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]1[N:20]=[N:21][N:22]=[C:15]1[CH:14]=[CH:13]2)C.FC1[N:34]=[C:33]([C:35]2([C:41]#[N:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=CC=1.CC(C)([O-])C.[K+]>CN(C=O)C>[N:20]1[N:16]2[C:17]3[C:12]([CH:13]=[CH:14][C:15]2=[N:22][N:21]=1)=[CH:11][C:10]([S:9][C:8]1[N:34]=[C:33]([C:35]2([C:41]#[N:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[CH:6][CH:7]=1)=[CH:19][CH:18]=3
Reactant: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nnnn32)c1
Reactant: N#CC1(c2cccc(F)n2)CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5nnnn54)c3)n2)CCOCC1
Temperature: 90 °C

Procedure:
9e (110 mg, 0.28 mmol) and 4-(6-fluoro-pyridin-2-yl)-tetrahydro-pyran-4-carbonitrile (9f, 60 mg, 0.28 mmol) were dissolved in DMF and degassed with N2 for 10 minutes. Potassium tert-butoxide (38 mg, 0.34 mmol) was added, and the reaction was degassed with N2 for another 10 minutes, and then heated to 90° C. for 2 hours. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography to obtain the desired product, 9g.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].C1(P([C:31]2[CH:36]=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]([O-])([O-:39])=[O:38].[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].CCO>[CH3:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:37]([O:39][CH2:36][CH3:31])=[O:38]
Reactant: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccsc1Br
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sccc1C
Temperature: 120 °C

Procedure:
2-Bromo-3-methylthiophene (Lancaster, 26.4 g, 0.149 mol), Pd(OAc)2 (0.213 g, 0.95 mmol), 1,3-bis(diphenylphosphino) propane (0.49 g, 1.2 mmol), Na2CO3 (21.1 g, 0.20 mol), and 200 mL abs EtOH were placed into a 450 mL Hastalloy-C stirred pressure reactor, purged with N2, then pressurized with 490 psig CO, and the stirring reactor was heated to 120° C. for 36 hrs. Analysis of the reaction mixture by gas chromatography showed 1.3% and 96.9% area % starting bromomethylthiophene and carbonylation product, respectively. After cooling and venting, the reactor contents were filtered and evaporated to give a light yellow oil/solid mixture. This residue was extracted with 1,2-dichloroethane and water, and the organic phase was evaporated to give an oil. Filtration of this oil to remove residual salt gave 20.7 g (81% wt. % yield) of orange oil as ethyl 3-methyl-2-thiophenecarboxylate. 13C NMR {1H} CDCl3: δ162.8, 145.9, 131.7, 129.9, 127.0, 60.6, 15.9, 14.4 ppm.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:25])([F:24])[CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[CH3:28][C:29](C)([O-])[CH3:30].[K+].BrCCC[C:38]1[CH:48]=[CH:47][CH:46]=[C:40]2[C:41]([NH:43][C:44](=[O:45])[C:39]=12)=[O:42]>CN(C)C=O>[C:41]1(=[O:42])[N:43]([CH2:28][CH2:29][CH2:30][N:13]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:12][CH2:11][C:10]([F:25])([F:24])[CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:44](=[O:45])[C:39]2=[CH:38][CH:48]=[CH:47][CH:46]=[C:40]12
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(S(=O)(=O)NCCC(F)(F)COCc2ccccc2)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CCC(F)(F)COCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of N-(4-benzyloxy-3,3-difluorobutyl)-p-toluenesulfonamide (63.17 g, 171.2 mmoles) and sodium iodide (3 g) in dry dimethylformamide (400 mL) is added solid potassium tert.-butoxide (19.2 g, 171 mmoles) with stirring at room temperature. The compound 3-bromopropylphthalimide (46 g, 171 mmoles) is added, and the mixture is stirred at room temperature overnight. The salts are filtered, and the filtrate is evaporated to dryness. The residue is taken up in dichloromethane (500 mL), filtered, and evaporated to dryness. Dissolving in ether (750 mL), washing with aqueous sodium bisulfite (10 g/250 mL), water (3×400 mL), drying (Na2SO4) and evaporation yields 1-phthalimido-4-p-toluenesulfonyl-7,7-difluoro-8-benzyloxy-4-aza-octane as a yellow oil (95.0 g, 99.8%). Traces of ether are removed by stripping twice with chloroform prior to using the material for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[NH:11])[NH:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:14](OC)(=O)[CH3:15].O>O1CCCC1>[CH3:14][C:15]1[O:10][N:9]=[C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])[N:11]=1
Reactant: N=C(NO)c1cccc(N)c1
Reactant: COC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(N)c2)no1
Temperature: 65 °C

Procedure:
To a stirred solution of Intermediate 18 (5.3 g) in dry tetrahydrofuran (50 ml) was added 4 Å molecular sieves, followed by sodium hydride (60% dispersion in mineral oil; 1.5 g) and the mixture heated at 65° C. for 30 min. After cooling to room temperature methyl acetate (2.8 ml) was added and the mixture heated under reflux for 16 h. After cooling to 20° C. the mixture was added to water (100 ml) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give the title compound as a white solid (4.0 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:11]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:12]=3[S:13][C:14]=2C(O)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C>[F:25][C:22]([F:23])([F:24])[C:18]1[C:12]2[S:13][CH:14]=[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)[C:11]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)N1CCC(c2c(C(=O)O)sc3c(C(F)(F)F)cccc23)CC1
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(c2csc3c(C(F)(F)F)cccc23)CC1
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
A mixture of 3-(1-acetyl-piperidin-4-yl)-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid (4.13 g, 11.1 mmol), Cu powder (0.706 g, 11.1 mmol), and quinoline (20 mL) was heated to 200° C. under nitrogen. After 10 min, no gas evolution was observed and the reaction cooled at room temperature. The mixture was diluted with ethyl acetate (100 mL), filtered through a Celite bed and the filtrate washed with 1 N HCl (2×100 mL), 5% aqueous potassium carbonate (100 mL), water (100 mL), and brine (100 mL) successively. The organics were dried over magnesium sulfate, filtered, and concentrated to give an amber oil. The oil was chromatographed on silica, eluting with 10% methanovethyl acetate to afford 2.69 g (74%) of the desired product as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)(=[O:38])=[O:37])[C:26]([Cl:44])=[CH:25][N:24]=1>>[Cl:44][C:26]1[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)(=[O:38])=[O:37])=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCCC4)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.072 g, 61%). MP: 68-88° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.42 (s, 1H), 8.54 (d, 1H, J=8.3 Hz), 8.13 (s, 1H), 7.97 (s, 1H), 7.93 (d, 1H, J=7.8 Hz), 7.55 (t, 1H, J=7.7 Hz), 7.47 (s, 1H), 7.21 (t, 1H, J=7.7 Hz), 6.65 (s, 1H), 3.86 (s, 3H), 3.58-3.50 (m, 2H), 3.48-3.40 (m, 2H), 3.33 (s, 6H), 3.29-3.23 (m, 4H), 3.07-2.98 (m, 1H), 2.87-2.75 (m, 6H), 2.74-2.68 (m, 2H). MS: 631.25 (MH)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.Cl.S(=O)=O>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:19])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: O=S=O
Product: O=C(Cl)c1cccc(Oc2ccccc2)c1

Procedure:
In a well ventilated hood, a mixture of m-phenoxy benzoic acid (200 g, 0.933 mole) (Aldrich) and thionyl chloride (105 mL, 1.44 moles) was placed in a one liter, round-bottomed flask. The flask was fitted with a magnetic stirring bar (or mechanical stirring bar for larger quantity preparation) and a reflux condenser with calcium chloride drying tube, which was attached to an exit tube, for evolved hydrogen chloride and sulfur dioxide, leading to a gas absorption trap. The mixture was heated on a heating mantle cautiously at first until a brownish-green solution was obtained (about 11/2 hours). The resulting solution was then heated gently for an additional 11/2 hours. The resulting brown solution was then cooled, and excessive thionyl chloride was distilled off at 40° C. To the resulting oil was added toluene (75 mL), and the solution was evaporated to remove a small amount of thionyl chloride. Addition and evaporation of toluene (75 mL) was repeated once more. The resulting acid chloride was then dissolved in 100 mL of tetrahydrofuran (THF dried over molecular sieves 3A), and ready to use freshly for reaction.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[C:17]2[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=2[CH:11]=[C:10]([CH:19]=[O:20])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][CH2:28][CH2:29]I>O>[F:27][CH2:28][CH2:29][N:13]1[C:12]2[CH:11]=[C:10]([CH:19]=[O:20])[CH:9]=[C:8]([O:7][CH3:6])[C:17]=2[O:16][CH2:15][C:14]1=[O:18]
Reactant: FCCI
Reactant: COc1cc(C=O)cc2c1OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc2c1OCC(=O)N2CCF
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
To 3 ml of a DMF solution containing 233 mg of 8-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboaldehyde [CAS No. 711021-34-0], 312 mg of potassium carbonate and 236 mg of 1-fluoro-2-iodoethane were added. The resulting mixture was stirred at room temperature for one day, and water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 4-(2-fluoroethyl)-8-methoxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboaldehyde (151 mg) as a white solid.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:19])([CH3:18])[CH2:13][CH2:12][C:11]([CH3:21])([CH3:20])[C:10]=2[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:22](Cl)(Cl)=[O:23].[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH2:1]([N:7]([C:8]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:19])([CH3:18])[CH2:13][CH2:12][C:11]([CH3:20])([CH3:21])[C:10]=2[CH:9]=1)[C:22](=[O:23])[NH:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:36][CH:37]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CCCCCCN(C(=O)Nc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 9 h
Yield: 28 %

Procedure:
A solution of hexyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (17) (635 mg, 2.21 mmole) in 10 mL toluene was treated with 1.0 mL of a 20% phosgene solution in toluene, stirred at room temperature for nine hours and then concentrated in vacuo. The residue was diluted with 15 mL of pyridine and treated with 730 mg of ethyl p-aminobenzoate (2 eq.). The reaction mixture was heated to 40° C. for 15 hours and concentrated in vacuo to provide a orange oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes, dry pack) to provide 296 mg (28%) of ethyl 4-[3-hexyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (19) as a yellow oil.
Reaction SMILES: [CH3:1][O-].[Na+].[Na].[OH:5][N:6]=[C:7]([SH:9])[CH3:8].[CH3:10][N:11]([CH3:32])[C:12](=[O:31])[C:13]([S:29][CH3:30])=[N:14][O:15][C:16]([N:18]([S:20][CH2:21][CH2:22][S:23][N:24]([C:26](F)=[O:27])[CH3:25])[CH3:19])=[O:17]>CO.C1(C)C=CC=CC=1>[OH:15][N:14]=[C:13]([S:29][CH3:30])[CH3:12].[CH3:10][N:11]([CH3:32])[C:12](=[O:31])[C:13]([S:29][CH3:30])=[N:14][O:15][C:16]([N:18]([CH3:19])[S:20][CH2:21][CH2:22][S:23][N:24]([CH3:25])[C:26]([O:5][N:6]=[C:7]([S:9][CH3:1])[CH3:8])=[O:27])=[O:17]
Reactant: C[O-]
Reactant: CSC(=NOC(=O)N(C)SCCSN(C)C(=O)F)C(=O)N(C)C
Reactant: CC(S)=NO
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: CSC(C)=NO
Product: CSC(C)=NOC(=O)N(C)SCCSN(C)C(=O)ON=C(SC)C(=O)N(C)C
Temperature: 25 °C

Procedure:
A solution of 0.8 g of N-hydroxy-ethanimidothioic acid, methyl ester in 5 ml methanol and 10 toluene was prepared, 0.4 g of sodium methoxide was added in one portion, and the mixture was stirred until dissolution was complete. The solution of the sodium salt of N-hydroxy-ethanimidothioic acid was added dropwise at 0° C. to a solution of 3.0 L g of 2-(dimethylamino)-N-[[[N-[[2-[N-(fluorocarbonyl)-N-methylaminothio]ethylthio]]-N-methylaminocarbonyloxy]]]-2-oxoethanimidothioic acid, methyl ester in 100 ml toluene. The resulting turbid reaction mixture was allowed to warm to ambient temperature and stirred 18 hrs. The reaction mixture was washed with two 100 ml portions of water, 100 ml of saturated sodium chloride solution, and dried over magnesium sulfate. Distillation of the solvent under reduced pressure gave a pale yellow viscous oil. The title compound was isolated from the crude reaction product by chromatography on silica gel employing ethyl acetate to elute the product. Using this procedure there was obtained 1.4 g of an oil that partially solidified. Suspension of the oily solid in a mixture of ether and hexanes gave 1.3 g of substantially pure 2-(dimethylamino)-N-[[[[N-methyl-N-[[[2-[[-N-methyl-N-[(1-methylthioethylidene)aminooxycarbonyl]aminothio]]ethylthio]]]aminocarbonyloxy]]]]-2-oxoethanimidothioic acid, methyl ester, m.p. 102°-106° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.[C:19]([C:21]1([OH:27])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]1)#[CH:20]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:27][C:21]1([C:19]#[C:20][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]4)[C:6]=3[CH:18]=2)[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]1
Reactant: C#CC1(O)CCN(C)C1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCC(O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)C1
Temperature: 100 °C
Yield: 9.9 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure E. In a solution of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (200 mg, 0.64 mmol) in acetonitrile (3 mL) and triethylamine (3 mL) were added, Pd(PPh3)2Cl2 (44 mg, 0.06 mmol), 3-Ethynyl-1-methyl-pyrrolidin-3-ol (160 mg, 1.3 mmol) and CuI (12 mg, 0.06 mmol). Then the solution was bubbled N2 for 5 min and heated by microwave for 1 h at 100° C. under nitrogen. The reaction mixture was filtered and the filtrate was purified by column to afford crude product. The crude product was purified by Prep HPLC to afford the titled compound (22.3 mg, 10%). 1H NMR (DMSO-d6, 400 MHz): δ 8.52 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.15 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.48 (s, 4H), 2.95 (m, 1H), 2.77 (m, 2H), 2.67 (m, 1H), 2.31 (s, 3H), 2.28 (m, 1H), 2.08 (m, 1H). LCMS=353.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH2:9][N:10]3[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:11]3)=[CH:7][O:8][C:4]=2[CH:3]=1.[C:22]([O-])([O-:24])=[O:23].[Cs+].[Cs+].Cl[C:29]1[S:30][C:31]2[C:32]([N:38]=1)=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=2>CN(C=O)C>[CH:22]([OH:24])=[O:23].[CH3:37][C:34]1[N:33]=[C:32]2[N:38]=[C:29]([O:1][C:2]3[CH:21]=[CH:20][C:5]4[C:6]([CH2:9][N:10]5[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:11]5)=[CH:7][O:8][C:4]=4[CH:3]=3)[S:30][C:31]2=[CH:36][CH:35]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2sc(Cl)nc2n1
Reactant: CC(=O)NC1CCN(Cc2coc3cc(O)ccc23)CC1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(Cc2coc3cc(Oc4nc5nc(C)ccc5s4)ccc23)CC1
Product: O=CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
To a suspension of N-[1-(6-hydroxy-benzofuran-3-ylmethyl)-piperidin-4-yl]-acetamide (50 mg, 0.17 mmol), Cs2CO3 (170 mg, 0.52 mmol) in DMF (1.73 mL) was added 2-chloro-5-methyl-thiazolo[4,5-b]pyridine (40 mg, 0.22 mmol) and the reaction mixture was stirred (rt, 16 h). The reaction mixture was filtered and purified via reverse-phase preparative HPLC to provide the title compound as a white solid (67 mg, 79%). MS (ESI): mass calcd. for C23H24N4O3S, 436.16; m/z found, 437.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.91 (d, J=8.1, 1H), 7.83 (5, 1H), 7.71 (d, J=8.3, 1H), 7.63 (5, 1H), 7.32 (d, J=7.9, 1H), 7.09 (d, J=8.1, 1H), 5.77 (5, 1H), 3.93 (5, 3H), 3.17 (5, 2H), 2.61 (5, 3H), 2.47 (5, 2H), 1.97 (5, 5H), 1.78 (5, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].CN1CCOCC1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][O:14][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 12 h

Procedure:
Combine (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (200 mg, 0.44 mmol) and N-methylmorpholine (0.97 mmol) in toluene (10 mL). Add dropwise, methanesulfonyl chloride (0.066 g, 0.57 mmol). After 12 hours, dilute with toluene (20 mL) and extract with 1M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate invacuo to give the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH2:7]=O.[N:9]1[N:10]2[CH:18]=[CH:17][CH:16]=[C:11]2[C:12]([NH2:15])=[N:13][CH:14]=1>C(O)(=O)C>[NH2:15][C:12]1[C:11]2=[CH:16][CH:17]=[C:18]([CH2:7][N:1]3[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]3)[N:10]2[N:9]=[CH:14][N:13]=1
Reactant: Nc1ncnn2cccc12
Reactant: C=O
Reactant: OC1CCNC1
Solvent: CC(=O)O
Product: Nc1ncnn2c(CN3CCC(O)C3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Pyrrolidinol (1.56 g, 17.9 mmol) and 37% formalin solution (1.45 g, 17.9 mmol) were dissolved in acetic acid (75 mL) and stirred at room temperature for 10 min. To this solution was added a solution of pyrrolo[2,1-f][1,2,4]triazin-4-amine (2.0 g, 14.9 mmol) in acetic acid (75 mL), and the mixture was stirred at 60° C. for 4 h. After evaporation, the residue was taken up in 200 mL of 1 N aqueous potassium carbonate solution and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (method 4) to give 390 mg (11% of th.) of the title compound.