Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:21]3[C:20]4[N:19]=[C:18]([S:22][CH3:23])[N:17]=[CH:16][C:15]=4[CH:14]=[CH:13][C:12]=3[C:11]([C:24]([NH2:26])=[O:25])=[N:10]2)[CH2:5][CH2:4]1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([NH:29][C:30]([NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:21]3[C:20]4[N:19]=[C:18]([S:22][CH3:23])[N:17]=[CH:16][C:15]=4[CH:14]=[CH:13][C:12]=3[C:11]([C:24]([NH2:26])=[O:25])=[N:10]2)[CH2:5][CH2:4]1)=[O:31])[CH3:28]
Reactant: CCN=C=O
Reactant: CSc1ncc2ccc3c(C(N)=O)nn(C4CCC(N)CC4)c3c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)NC1CCC(n2nc(C(N)=O)c3ccc4cnc(SC)nc4c32)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 11.1 %

Procedure:
30 mg (0.084 mmol) of 1-(4-aminocyclohexyl)-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride were dissolved in 2 ml of dimethylformamide. To the obtained solution 32 μl (0.42 mmol) of ethylisocyanate, 60 μl (0.336 mmol) of DIPEA, were added. The mixture was stirred at 100° C. for 18 hours, the solution was portioned between ethyl acetate and saturated aqueous solution of NaHCO3, and the organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum. The crude was purified by silica gel chromatography (DCM/MeOH/NH4OH 95/5/1) to provide 1-{4-[(ethylcarbamoyl)amino]cyclohexyl}-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide 4 mg (11%) as a white solid. LC/MS (254) HPLC method 2 Rt 4.38 min. 1H NMR (401 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.27 (d, J=8.67 Hz, 1H), 7.74 (d, J=8.67 Hz, 1H), 7.59 (s, 2H), 6.06 (d, J=7.08 Hz, 1H), 5.89-6.02 (m, 1H), 5.81 (t, J=5.49 Hz, 1H), 3.78-3.88 (m, 1H), 3.00-3.07 (m, 2H), 2.71-2.74 (m, 3H), 2.15-2.29 (m, 2H), 1.99-2.11 (m, 3H), 1.90 (dd, J=3.54, 13.67 Hz, 2H), 1.65-1.79 (m, 2H), 1.01 (t, J=7.20 Hz, 3H). HRMS (ESI) calcd for C20H25N7O2S [M+H]+ 428.1863 found 428.1852.
Reaction SMILES: [I-:1].O[CH2:3][P+:4]([CH2:9]O)([CH2:7]O)[CH2:5]O.[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14]>C1(C)C=CC=CC=1>[I-:1].[CH3:11][N:12]([CH2:9][P+:4]([CH2:3][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])([CH2:5][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[CH2:7][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)NC
Reactant: OC[P+](CO)(CO)CO
Agent: [I-]
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C[P+](CN(C)C(=O)NC)(CN(C)C(=O)NC)CN(C)C(=O)NC
Yield: 97.1 %

Procedure:
Reaction of tetrakis(hydroxymethyl)phosphonium iodide (7.05 g, 0.025 mol) with 1,3-dimethylurea (8.81 g, 0.1 mol) in toluene (25 ml), following Example 1, gave 13.65 g (97.1%) of tetrakis(1,3-dimethylureidomethyl)phosphonium iodide (I, R=R'=CH3, R"=H, X=I) as a white, crystalline solid, mp 194° C. dec after two recrystallizations from ethanol (10 mg/g). The product suffered no weight loss when dried under vacuum for 2 hr at 100° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH2:30]([CH2:32][NH2:33])[OH:31]>CO>[OH:31][CH2:30][CH2:32][NH:33][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: NCCO
Reactant: O=C1CCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)CC1
Solvent: CO
Product: O=C(Nc1cccc(CN2CCC(NCCO)CC2)n1)Nc1csc(-c2ccncc2)n1

Procedure:
N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(piperidon-4-yl)methyl]urea (60 mg, 0.147 mmol, Example 175) and ethanolamine (0.09 mL, 1.47 mmol) were heated in MeOH (10 mL) yielded the title compound as pale yellow solid. MS m/z: 454.6 (M+H). Calc'd. for C22H27N7O2S-453.57.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][O:20][CH2:21][C:22]#[CH:23])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:29](=[O:31])=[O:30].C(O)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][O:20][CH2:21][C:22]#[C:23][C:29]([OH:31])=[O:30])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: C#CCOCc1c(C)nc2c(OCc3ccccc3)cccn12
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc2c(OCc3ccccc3)cccn2c1COCC#CC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
To a solution of 8-benzyloxy-3-(2-propynyloxymethyl)-2-methylimidazo[1,2-a]pyridine (1 g) in tetrahydrofuran (10 ml) was added dropwise 10% solution of n-butyllithium in n-hexane (2.09 ml) at -60° C. under a nitrogen atmosphere. After being stirred for 10 minutes the solution was treated with dry ice (1.4 g), allowed to warm to room temperature, and acidified with diluted acetic acid. The resulting precipitates were collected by filtration, washed with water, and recrystallized from methanol to give 8-benzyloxy-3-(3-carboxy-2-propynyloxymethyl)-2-methylimidazo[1,2-a]pyridine (0.67 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:17]1([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.N1(C2C3CCCCC=3N=CC=2)CCNCC1>C(#N)C>[N:26]1[C:27]2[CH2:28][CH2:29][CH2:30][CH2:31][C:32]=2[C:23]([N:17]2[CH2:18][CH2:19][N:20]([CH2:2][C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:21][CH2:22]2)=[CH:24][CH:25]=1
Reactant: c1ccc2c(N3CCNCC3)ccnc2c1
Reactant: COC(=O)COc1ccc(C(=O)CBr)cc1
Agent: c1cc(N2CCNCC2)c2c(n1)CCCC2
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccnc4c3CCCC4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a similar manner to Example 1, methyl 4-bromoacetylphenoxyacetate (1.23 g), a 1:1 mixture containing 4-(1-piperazinyl)quinoline and 4-(1-piperazinyl)-5,6,7,8-tetrahydroquinoline (1.84 g) and acetonitrile (56 ml) yielded, after stirring at room temperature overnight, filtration and evaporation of the filtrate, an orange/brown oily residue which was purified by flash chromatography, first on neutral alumina by elution with 5% v/v methanol/dichloromethane, then on silica by elution with methanol/dichloromethane (0.5% v/v to 5% v/v), and finally by crystallisation of the lower Rf material from methanol/water, to yield the title compound (298 mg) as a cream solid: NMR (CDCl3) δ 1.76(2H,m), 1.89(2H,m), 2.64(2H,m), 2.76(4H,m), 2.95(2H,m), 3.07(4H,m), 3.80(2H,s), 3.81(3H,s), 4.71(2H,s), 6.68(1H,d), 6.95(2H,d), 8.03(2H,d), 8.28(1H,d); m/Z 424 (M+H)+ ; calculated for C24H29N3O4.1.0 H2O: C, 65.3%; H, 7.08%; N, 9.52%; found: C, 65.6%; H, 6.7%; N, 9.3%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:31]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:31][CH2:9][C:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(C)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(C(=O)CBr)cn1
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a chloroform (6.5 mL) solution of 1-(6-methylpyridin-3-yl)ethanone (0.43 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (0.63 mL) and trimethylsilyl trifluoromethanesulfonate (0.69 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (0.63 g) was added thereto, and the resultant was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the resultant was stirred for 15 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=90/10→70/30) to obtain the title compound (0.24 g) as a light brown solid.
Reaction SMILES: C([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH:10]([O:12]C(C)(C)C)[CH2:9][NH:8]1)(C)(C)C.C(OC(=O)[C@@H]1CCCN1)(C)(C)C.[C:30]([S:33][CH2:34][CH2:35][C:36](Cl)=[O:37])(=[O:32])[CH3:31].C(SCC(C)C(Cl)=O)(=O)C>>[C:30]([S:33][CH2:34][CH2:35][C:36]([N:8]1[CH2:9][CH:10]([OH:12])[CH:11]=[C:7]1[C:6]([OH:5])=[O:17])=[O:37])(=[O:32])[CH3:31]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(OC(C)(C)C)CN1
Agent: CC(=O)SCC(C)C(=O)Cl
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Product: CC(=O)SCCC(=O)N1CC(O)C=C1C(=O)O

Procedure:
By substituting 4-tert-butoxy-L-proline tertbutyl ester for the L-proline tert-butyl ester and 3-acetylthiopropanoyl chloride for the 3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1, 1-(3-acetylthio-1-oxopropyl)-4,5-dihydro-4-hydroxy-1H-pyrrole-2-carboxylic acid is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Br[N:13]1C(=O)CC[C:14]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C-]#N.[Na+].C(=O)(O)[O-].[K+]>C(Cl)(Cl)(Cl)Cl.CN(C)C=O>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH2:1][C:14]#[N:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ncccc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#CCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
A solution of 6-methyl-quinoline (3.00 g, 20.6 mmol), N-bromosuccinimide (3.96 g, 22.0 mmol), and benzoyl peroxide (0.51 g, 2.10 mmol) in carbon tetrachloride (100 mL) is stirred at reflux for 2 h. The reaction is cooled to room temperature then washed with saturated aqueous sodium bisulfite (50 mL). The organic phase is passed through 30 g SiO2 (2×) eluting with dichloromethane then diethyl ether. N,N-Dimethylformamide (83 mL) is added to the combined organic fractions and solvent removed under reduced pressure leaving only the reaction mixture in N,N-dimethylformamide. To the reaction mixture in N,N-dimethylformamide is added sodium cyanide (1.22 g, 24.9 mmol) and potassium bicarbonate (2.51 g, 24.9 mmol). The reaction mixture is allowed to stir at 50° C. for 2 h. The cooled reaction mixture is poured into pH 7 buffer (75 mL) and extracted with ethyl acetate (2×100 mL). The organic layers are combined, washed with saturated aqueous sodium chloride (100 mL), dried over solid sodium chloride, and concentrated under reduced pressure to afford an oil that is purified by normal phase flash chromatography (120 g Biotage KP-Sil 40L: 10% ethyl acetate in hexanes for 5 min, 20% ethyl acetate in hexanes for 20 min, 40% ethyl acetate in hexanes for 20 min, 60% ethyl acetate in hexanes for 20 min, then 60-100% ethyl acetate in hexanes ramp over 20 min) to provids 645 mg (18%) of the title compound. MS ES+ m/e 169 (M+1).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([O:42][CH3:43])[CH:36]=1.CN(C)C=O>C(OC)(C)(C)C.O>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][CH2:13][C:4]2=[O:3])=[CH:36][C:37]=1[O:42][CH3:43]
Reactant: COc1cc(Br)ccc1Cl
Reactant: C[Si](C)(C)OC1=Cc2ccccc2CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2C(=O)CCc3ccccc32)ccc1Cl
Temperature: 90 °C

Procedure:
Charge an oven dried, argon flushed 25-mL 2-necked round bottomed flask equipped with a stirring bar and reflux condenser with 2-trimethylsilyloxy-3,4-dihydronaphthalene (0.4247 grams, 1.9449 mmoles) and tetra-n-butylammonium fluoride (2.3 mL, 2.30 mmoles, 1 M in tetrahydrofuran), stir for a few minutes and then add 4-bromo-2-methoxy-1-chlorobenzene (0.4336 grams, 1.9577 mmoles) dichlorobis(tri-ο-tolyl-phosphine)palladium (0.0154 grams, 0.0196 mmoles) and 5 mL dimethylformamide. Heat the reaction mixture for 18 hours (oil bath temperature about 90° C.), cool to RT and add 5 mL water and 10 mL t-butylmethyl ether. Separate the layers, extract the aqueous layers with 3×5 mL t-butylmethyl ether, wash the combined organic layers with water and saturated salt solution, dry over magnesium sulfate and concentrate using a Buchi rotavapor to yield the final product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:16]#[C:17][CH2:18][CH2:19][CH3:20].O>O1CCCC1.[Cu]I.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([C:16]#[C:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(I)ccn1
Reactant: C#CCCC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccnc(F)c1
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a cold (0° C.) solution of 2-fluoro-4-iodopyridine (1.0 g, 4.5 mmol) in tetrahydrofuran (15 mL) was added copper (I) iodide (86 mg, 0.45 mmol), dichlorobistriphenylphosphine palladium (II) (157 mg, 0.22 mmol), and triethylamine (1.8 mL, 13.4 mmol). Pentyne (0.88 mL, 8.9 mmol) was added dropwise to the reaction mixture and the resultant solution was stirred at 0° C. for 30 minutes and then at room temperature for 18 hours. Water and ether were added and the layers separated. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed flash chromatography on silica gel (5:1 hexane-ether) provided 2-fluoro-4-pent-1-ynylpyridine (670 mg, 92%) as a clear oil. 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.11 (d, 1H), 6.88 (s, 1H), 2.41 (t, 2H), 1.63 (m, 2H), 1.04 (t,3H),; 19F NMR (CDCl3) δ −68.68; MS m/z 164 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH:16]=[CH2:17]>CC(C)=O>[CH2:17]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:16]=[CH2:15]
Reactant: Oc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
94 g phenol (1 mol), 155 g anhydrous potassium carbonate (1.2 mol) and 300 mL acetone were added to a three-necked bottle, and stirred at 50° C. for 10 minutes. 107 g 3-bromopropylene (0.9 mol) was added dropwise, then the mixture was refluxed for 2 hours. After acetone was evaporated under reduced pressure, water was added to the residual solution and a solid was isolated. After sucked filtration, 108 g solid was obtained. Yield: 90.1%. MS: 135 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.Cl.Cl.[N:34]1([CH:39]2[CH2:42][NH:41][CH2:40]2)[CH:38]=[CH:37][N:36]=[CH:35]1.C(N(C(C)C)CC)(C)C>C(#N)C.CO>[N:34]1([CH:39]2[CH2:42][N:41]([C:27]([C@@H:11]3[CH2:10][C@H:9]([S:8][CH2:7][C:6]4[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:13][N:12]3[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])=[O:28])[CH2:40]2)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: c1cn(C2CNC2)cn1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(n4ccnc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
3.80 g of (2S, 4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid were dissolved in 40 ml of dry acetonitrile. 1.65 g of N,N'-carbonyldiimidazole were added to the resulting solution, and the mixture was stirred at 40° C. for 1 hour. A solution of 2.00 g of 3-(1-imidazolyl)azetidine dihydrochloride [prepared as described in step (b) above] and 2.90 g of diisopropylethylamine dissolved in a mixture of 30 ml of dry acetonitrile and 5 ml of methanol was then added at room temperature to the reaction mixture, after which the mixture was stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 4.00 g of the title compound, as a powder, from the fraction obtained by elution with an 85:15 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][C:13]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.CO.[NH3:34].CC(O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:34])[N:17]=3)=[CH:14][C:13]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(Nc2ncc(CN3CCOCC3)cc2-c2nc(C)nc(SC)n2)cn1
Solvent: CC(C)O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(CN3CCOCC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 90 °C
Yield: 34 %

Procedure:
A stirred mixture of N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-5-(morpholinomethyl)pyridin-2-amine (19 mg, 0.043 mmol) in 2.0 M NH3/iPrOH (3.0 mL) was sealed and heated at 90° C. for 24 h. The reaction mixture was concentrated and the crude product was adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (DCM to 5% MeOH in DCM) to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (6.00 mg, 0.015 mmol, 34.0% yield) as a yellow solid. LCMS (API-ES) m/z 409 (M+H)+; 1H NMR (400 MHz, CDCl3, with one drop of d6-DMSO) δ 11.69 (br. s., 1H) 8.76 (br. s., 1H) 8.39 (br. s., 1H) 8.23 (br. s., 1H) 8.12 (br. s., 1H) 6.77 (d, J=9.00 Hz, 1H) 5.92 (br. s., 2H) 3.93 (br. s., 3H) 3.49 (br. s., 2H) 2.55 (br. s., 3H) 2.50 (br. s., 4H) 2.23 (br. s., 4H).
Reaction SMILES: [C:1](#[N:4])[CH2:2]C.C(N(C(C)C)CC)(C)C.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=1)([O-:16])=[O:15].[I-].C(C[P+](C)(C)C)#N.Cl>C(OCC)(=O)C.O>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][CH2:2][C:1]#[N:4])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CCC#N
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCc1ccc([N+](=O)[O-])cc1
Temperature: 97 °C

Procedure:
Propionitrile (32 mL), diisopropylethylamine (2.5 g, 19.58 mmol) were added to a mixture of 4-nitrobenzyl alcohol (1 g, 6.53 mmol) and (cyanomethyl)trimethylphosphonium iodide (4 g, 16.32 mmol). The mixture was heated at 97° C. for 24 h. Water (1 mL) was added to the mixture and followed by conc. HCl (5 mL). Ethyl acetate (3×100 mL) was used to extract the product. Organic layer was washed with brine, dried with sodium sulfate, concentrated to give dark brown solid. The crude product was purified by flash column chromatography (Ethyl acetate:Hexanes 1:1) to give 740 mg of 3-(4-nitrophenyl)propionitrile as a light orange solid. 1H NMR (DMSO-d6): δ 8.20-8.17 (dd, J=8.7 Hz, 2H), 7.59-7.56 (d, J=9.0 Hz, 2H), 3.06-3.01 (m, 2H).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]=1Br)=[O:12])[CH2:3]2.C(=[NH:36])(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[ClH:1].[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:22]([NH2:36])=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1sc2ccccc2c1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Product: Nc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
87 mg (0.22 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzo-thiopene-2-carboxamide hydrochloride, 47.1 mg (0.26 mmol) of benzophenone-imine, 12.1 mg (0.02 mmol) of rac-BINAP, 45.8 mg (0.48 mmol) of sodium tert-butoxide and 6.0 mg (0.01 mmol) of Pd2(dba)3 are, under argon, added to a flask which has been dried by heating. 1.5 ml of toluene are added, and the reaction mixture is heated at 80° C. After 30 min, 0.5 ml of THF is added, followed by a further 6.0 mg (0.01 mmol) of Pd2(dba)3 after 6 h. After a further 6 h, the mixture is filtered (0.45 μm filter) and then purified by preparative HPLC. The resulting benzophenoneimine adduct is dissolved in a 1:1 mixture of THF and methanol with addition of 20% by volume of 1N hydrochloric acid. After 1 h at RT, the reaction mixture is concentrated. The solid formed is triturated with acetonitrile and filtered off. Drying under high vacuum gives 17 mg (21% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([OH:26])[C:22]([F:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].O>CN(C)C=O>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[C:20]([F:27])=[C:21]([C:22]([F:25])=[CH:23][CH:24]=2)[O:26][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: Oc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c(F)ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)c1F
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
To a suspension 3-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11-yl)-2,6 difluoro-phenol (0.200 g, 0.453 mmol) and potassium carbonate (0.085, 0.612 mmol) in N,N-dimethylformamide (2 mL) was added methyl bromoacetate (0.086 mL, 0.906 mmol) dropwise at room temperature under a dry nitrogen atmosphere. After stirring 2.5 hours the reaction mixture was combined with water (50 mL) and the organics were extracted with ether. The extract was combined with silica gel, the solvent was removed and the adsorbate was flash chromatographed (90/10 petroleum ether/ethyl acetate). The solvents were chased with benzene (2×) and petroleum ether to give [3-(6-bromo-benzo[b]naphtho[2, 3-d]thiophen-11-yl)-2, 6-difluoro-phenoxy]-acetic acid, methyl ester as a white solid (0.198 g, 85%). To a solution of this methyl ester (0.190 g, 0.370 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL) was added a 1 N aqueous solution of potassium hydroxide (0.55 mL, 0.55 mmol) dropwise at room temperature. After stirring 1 hour the solvents were removed and water was added to the solid residue. The aqueous mixture was acidified with 10% HCl and the organics were extracted with ether. After several minutes of vigorous shaking the layers were separated and the organic layer was washed with water and concentrated. The residue was chased with benzene and dried in vacuo to give the title compound as a white solid (0.177g, 95%): mp 195-197° C.: NMR (400 MHz, DMSO-d6): 8 13.11 (broad s, 1 H), 8.31 (d, J=8 Hz, 1 H), 8.09 (d, J=8 Hz, 1 H), 7.83-7.79 (m, 1 H), 7.64-7.46 (m, 4 H), 7.31-7.27 (m, 1 H), 7.23-7.17 (m, 1 H), 6.81 (d, J=8 Hz, 1 H), 4.89 (s, 2 H); MS(-FAB): (M-H): one bromine pattern observed: 497/499 (35%138%); HRMS: Calc. for C24H13BrF2O3S M+: 497.97368, measured mass: 497.97787, mass deviation 4.19 mmu; Anal. HPLC 97% pure; Anal. Calc. for C24H13BrF203S: C, 57.72, H, 2.62% N, 0.00. Found: C, 56.77, H, 2.79% N, 0.00.