Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:29][CH2:30][O:31][CH2:32][CH3:33])[CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[CH2:32]([O:31][CH2:30][CH2:29][N:27]([C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH3:28])[CH3:33]
Reactant: CCOCCN(C)c1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g), 4-[N-(2-ethoxyethyl)-N-methylamino]phenyl borate (0.17 g), potassium carbonate (0.2 g), water (1.1 ml), ethanol (1.1 ml) and toluene (10.7 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.03 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.22 g) as colorless amorphous.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(Br)C1C=CC=CC=1>[CH2:23]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=2[C:6]2[C:14]1=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc2c3c([nH]c12)CCCC3=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: Cc1cccc2c3c(n(Cc4ccccc4)c12)CCCC3=O
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
8-Methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.1967 g, 0.99 mmol) is added to a slurry of pentane-washed NaH (0.0485 g, 0.0012 mol) in DMF (2 mL) and after stirring for 30 min, benzyl bromide (0.14 mL, 0.0012 mol) is added. After 3 h starting material still remained, so additional benzyl bromide (0.015 mL, 0.013 mmol) is added and the mixture is stirred overnight at room temperature. The mixture is then partitioned between aq. sodium bicarbonate and ethyl acetate and the organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are recrystallized from ethyl acetate/hexane/dichloromethane to give 0.2076 g (73%) of the title compound; mp 165-166° C.; MS (ESI+) for C20H19NO m/z 290.2 (M+H)+; IR (drift) 2940, 1637, 1599, 1538, 1494, 1462, 1447, 1416, 1357, 1322, 1121, 787, 752, 727, 697 cm−1; 1H NMR (CDCl3) δ2.21, 2.51, 2.59, 2.82, 5.58, 6.89, 6.95, 7.16, 7.29, 8.23. Anal. Calcd for C20H19NO: C, 83.01; H, 6.62; N, 4.84. Found: C, 82.53; H, 6.62; N, 4.86.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:10]([C:20](O)=[O:21])=[C:11]([CH2:15][O:16][CH2:17][CH2:18][Cl:19])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2].CCN=C=NCCCN(C)C.Cl.[C:42]1([CH:48]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:49][CH2:50][NH2:51])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:10]([C:20](=[O:21])[NH:51][CH2:50][CH2:49][CH:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[C:11]([CH2:15][O:16][CH2:17][CH2:18][Cl:19])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2]
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)O)=C(COCCCl)N1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCCl)N1

Procedure:
250 mg (0.560 mmol) of 2-(2-chloroethoxy) methyl-4-(3-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 5-(2-cyanoethyl) ester, 110 mg (0.570 mmol) of WSC hydrochloride and 120 mg (0.570 mmol) of 3,3-diphenylpropylamine were stirred at room temperature for 15 hours in 4 ml of dichloromethane. After evaporating dichloromethane under reduced pressure, 0.1 N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19](O)=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C)C=O>[C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([Cl:26])=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1
Reactant: Cc1ccc(NS(=O)(=O)c2cccc(C=CC(=O)O)c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)c2cccc(C=CC(=O)Cl)c2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a suspension of 3-(3-p-tolylsulfamoyl-phenyl)-acrylic acid (5d) (0.75 g, 2.36 mmol) in dichloromethane (10.0 ml): oxalyl chloride (0.62 ml, 7.08 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.79 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:8][S:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[S:4][CH2:3]1.[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)CCl>[CH3:15][C:14]([C:10]1[CH:11]=[CH:12][C:5]2[S:4][CH2:3][C:2]([CH3:13])([CH3:1])[CH2:8][S:7][C:6]=2[CH:9]=1)=[O:16]
Reactant: CC(=O)Cl
Reactant: CC1(C)CSc2ccccc2SC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)SCC(C)(C)CS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13.3 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepine were dissolved in 110 ml of ethylene chloride under argon and treated portionwise at -10° C. in succession with 10.1 ml of acetyl chloride and 19 g of aluminum chloride. Thereafter, the reaction mixture was stirred at room temperature for 21/2 hours, poured on to ice and extracted with ether. The extract was washed with dilute sodium hydroxide solution and water, dried and evaporated to dryness. There were obtained 15.6 g of 3,4-dihydro-3,3-dimethyl-2H-1,5-benzodithiepin-7-yl methyl ketone in the form of brownish crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][NH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH3:12][C:13]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:32][C:19]=2[N:18]=1)([CH3:16])[CH2:14][CH3:15]>C1COCC1>[CH3:16][C:13]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33]([N:7]3[CH:8]=[CH:9][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:6]3)(=[O:35])=[O:34])=[CH:32][C:19]=2[N:18]=1)([CH3:12])[CH2:14][CH3:15]
Reactant: CNC(=O)c1cc[nH]c1
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NC)c3)ccc2n1CC1CCOCC1
Yield: 61.6 %

Procedure:
Following the same procedure in Example 29, using N-methyl-1H-pyrrole-3-carboxamide (57 mg, 0.46 mmol) (see following step B for preparation), sodium hydride (110 mg, 60%, 2.76 mmol), 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (352 mg, 0.92 mmol) in THF (10 mL). The crude product was purified by MPLC using EtOAc on silica gel to give 134 mg (62%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.77 (t, J=7.42 Hz, 3 H), 1.40-1.56 (m, 4 H), 1.59 (s, 6 H), 1.94 (q, J=7.42 Hz, 2 H), 2.19-2.37 (m, 1 H), 2.79 (s, 3 H), 3.24-3.36 (m, 2 H), 3.84-3.94 (m, 2 H), 4.41 (d, J=7.62 Hz, 2 H), 6.63 (dd, J=3.32, 1.56 Hz, 1 H), 7.29 (dd, J=3.32, 2.34 Hz, 1 H), 7.78 (dd, J=2.15, 1.76 Hz, 1 H), 7.88-7.92 (m, 1 H), 7.92-7.98 (m, 1 H), 8.26 (dd, J=1.56, 0.59 Hz, 1 H); MS (ESI) (M+H)+=473.0; Anal. Calcd for C24H32N4O4S+1.0 TFA (586.63): C, 53.23; H, 5.67; N, 9.55. Found: C, 53.28; H, 5.77; N, 9.42.
Reaction SMILES: C([O:8]C(N1C(C(N(C(=O)[C@H](CC2N=CNC=2)N)N)=O)CC2C3C(=CC=CC=3)NC=2C1)=O)C1C=CC=CC=1.[CH2:38]([O:45][C:46]([N:48]1[CH:60]([C:61]([NH:63][C@H:64]([C:71]([NH:73][C@H:74]([CH:79]=NNC(N)=O)[CH2:75][CH:76]([CH3:78])[CH3:77])=[O:72])[CH2:65][C:66]2[N:70]=[CH:69][NH:68][CH:67]=2)=[O:62])[CH2:59][C:58]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][C:50]=2[CH2:49]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([O:45][C:46]([N:48]1[CH:60]([C:61]([NH:63][C@H:64]([C:71]([NH:73][C@H:74]([CH:79]=[O:8])[CH2:75][CH:76]([CH3:78])[CH3:77])=[O:72])[CH2:65][C:66]2[N:70]=[CH:69][NH:68][CH:67]=2)=[O:62])[CH2:59][C:58]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[NH:51][C:50]=2[CH2:49]1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N(N)C(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Product: CC(C)C[C@@H](C=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1

Procedure:
The procedure described in Example 1(a) was repeated, but using 125 mg. (0.25 mmole) of N-(2-benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carbolin-3-ylcarbonyl)-L-histidine hydrazide. There were obtained 120 mg. of N-(2-benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carbolin-3-ylcarbonyl)-L-histidyl-L-leucinal semicarbazone. This product was then treated in the same way as in Example 1(b) by partition chromatography using Sephadex G-25, to give 67 mg. of the desired compound as a white powdery solid, melting at 126°-130° C.; [α]22 +21.6° (C`0.5, methanol).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=O)[N:11]=2)[CH:6]=1.NC1SC=C(C(OCC)=O)N=1.[H-].[Na+].N(C(C)C(OC)OC)=C=S.OS(O)(=O)=O.OO.[C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])(=[O:49])[CH3:48].[Li]>CC(O)=O.CCO.CN(C=O)C>[C:51]([O:50][C:47](=[O:49])[CH2:48][C:12]([C:10]1[N:11]=[C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)[S:8][CH:9]=1)=[O:14])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1csc(-n2cnc(C)c2)n1
Agent: CCOC(=O)c1csc(N)n1
Agent: COC(OC)C(C)N=C=S
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cn(-c2nc(C(=O)CC(=O)OC(C)(C)C)cs2)cn1

Procedure:
Prepared from ethyl 2-(4-methyl-imidazol-1-yl)-thiazole-4-carboxylate [prepared from ethyl 2-amino-4-thiazolecarboxylate (CAS-No. [256420-32-3]) by the following synthetic sequence: 1.) NaH, 2-isothiocyanato-1,1-dimethoxy-propane, DMF, 23° C.; 2.) aq. H2SO4, reflux; 3.) EtOH, conc. H2SO4, 23° C.; 4.) 30% H2O2, HOAc, 23° C.] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a brown oil (8.73 g).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4](O)[C@H:2]1O.[H][H]>[Pd]>[C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[CH2:4][CH2:2]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1

Procedure:
In Step 4, inosine derivative (IV') is subjected to reduction with hydrogen (H2) in an organic solvent over a palladium catalyst. This reduction proceeds with minimum substrate decomposition. This is followed by hydrolysis or ester exchange reaction, giving 2',3'-dideoxyinosine derivative (A').
Reaction SMILES: N.[C:2]([O:6][C:7]([C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C[N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CS(C)=O>[C:2]([O:6][C:7]([C:9]1([C:14]([NH2:18])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(C(=O)O)CCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C1(C(N)=O)CCCC1
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 2 M methanolic ammonia (3.3 mL) was added to a stirred solution of 1-(tert-butoxycarbonyl)cyclopentanecarboxylic acid (1.0 g, 4.36 mmol), TEA (3.65 mL, 0.0262 mol), and TBTU (1.61 g, 5 mmol) in DMSO (5 mL) at 22° C. After stirring for 1 hr the solution was poured into ice cold water. The mixture was extracted with ethyl acetate. The extract was washed with brine (2×), dried over MgSO4 and concentrated to leave a colorless solid. Recrystallization from ethyl acetate-hexanes afforded 1-(tert-butoxycarbonyl)cyclopentanecarboxamide (660 mg, 66%). TFA (2.5 mL) was added to a stirred solution of the amide (445 g) in methylene chloride (2.5 mL). The solution was stirred for 1 hr at 22° C. and then concentrated to an oil. Trituration with diethyl ether afforded the TFA salt ofl-aminocyclopentanecarboxamide as a colorless solid. Coupling of the amine with, 13-cyclohexyl-6,7-dihydro-6-oxo-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid afforded the titled compound. MS m/z 486 (MH+); 1H NMR (300 MHz, DMSO-D6) δ ppm 1.09-2.29 (m, 8 H) 2.42-2.56 (m, 2 H) 2.86 (s, 1 H) 4.61 (s, 1 H) 4.97-5.17 (m, 1 H) 6.73 (s, 1 H) 7.03 (s, 1 H) 7.29 (d, J=7.68 Hz, 1 H) 7.38 (t, J=7.50 Hz, 1 H) 7.50 (t, J=7.50 Hz, 2 H) 7.61 (d, J=9.51 Hz, 1 H) 7.88 (d, J=8.78 Hz, 1H) 8.28 (s, 1 H).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.S(Cl)(Cl)=O.[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[C:33]([N:34]=2)=[CH:32][CH:31]=[C:30]([Sn](C)(C)C)[N:29]=3)=[C:22]([F:39])[CH:21]=1>C1(C)C=CC=CC=1>[O:16]1[CH2:17][CH2:18][CH2:19][O:14][CH:15]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[C:33]([N:34]=2)=[CH:32][CH:31]=[C:30]([C:6]([CH:4]2[CH2:3][C:2]([F:1])([F:9])[CH2:5]2)=[O:8])[N:29]=3)=[C:22]([F:39])[CH:21]=1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: C[Sn](C)(C)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CC(F)(F)C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 3,3-difluorocyclobutanecarboxylic acid (542.6 mg, 3.99 mmol) in thionyl chloride (5.24 mL, 71.8 mmol) was heated at 70° C. for 1 h and then concentrated in vacuo. 2-(4-(1,3-Dioxan-2-yl)-2-fluorophenyl)-5-(trimethylstannyl)thiazolo[5,4-b]pyridine (1.08 g, 2.254 mmol) was added to the residue, and the mixture was taken up in toluene (20.0 mL) and stirred under argon at 80° C. for 16 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (0-60% EtOAc/hexanes) to provide (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridin-5-yl)(3,3-difluorocyclobutyl)methanone as an off-white solid. MS (ESI) m/z: Calculated: 434.1; Observed: 435.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-].[CH2:12]([N+:19](C)(C)C)[C:13]1C=CC=C[CH:14]=1>C(#N)C=C.C(OCC)C>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([O:10][CH2:14][CH2:13][C:12]#[N:19])=[CH:3][C:2]=1[CH3:1]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: COc1ccc(O)cc1C
Agent: [OH-]
Solvent: C=CC#N
Solvent: CCOCC
Product: COc1ccc(OCCC#N)cc1C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 7.0 grams (0.050 mole) of 3-methyl-4-methoxyphenol (known compound) in 20 mL of acrylonitrile was stirred, and 0.4 mL of benzyltrimethylammonium hydroxide (Triton® B) was added. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred during a 21 hour period. The reaction mixture was then cooled to ambient temperature and diluted with 100 mL of diethyl ether. The mixture was then first washed with three 50 mL portions of an aqueous solution of 10% potassium hydroxide, then with three 50 mL portions of aqueous 4N hydrochloric acid. The organic layer was dried with sodium sulfate, and the mixture was filtered. The filtrate was concentrated under reduced pressure, yielding 6.0 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C@@H:8]2[CH2:11][CH2:10][C@H:9]2[C:12]([OH:14])=O)=O)=[CH:4][CH:3]=1.[NH:17]([CH2:19][CH:20]([OH:23])[CH2:21][CH3:22])[NH2:18].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:8]3[CH:9]([C:12](=[O:14])[N:17]([CH2:19][CH:20]([OH:23])[CH2:21][CH3:22])[N:18]=2)[CH2:10][CH2:11]3)=[CH:15][CH:16]=1
Reactant: O=C(O)[C@@H]1CC[C@H]1C(=O)c1ccc(Cl)cc1
Reactant: CCC(O)CNN
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(O)CN1N=C(c2ccc(Cl)cc2)C2CCC2C1=O
Temperature: 25 °C

Procedure:
Into a flask equipped with a stirrer, heating mantle and Dean - Stark water separator is charged 7.2 g (0.30 mole) of a mixture of cis-and trans-2-p-chlorobenzoylcyclobutane carboxylic acid, 3.5 g (0.033 mole) of 1-hydrazino-2-butanol and 100 ml. of toluene. The mixture is stirred and refluxed until the water layer in the Dean-Stark tube remains constant (ca. 5hr). The solvent is removed in vacuo on a rotary evaporator, and the residue is dissolved in hot diethyl ether and allowed to cool to room temperature. The resultant solid is filtered off and yields 2-(p-chlorophenyl)-4-(2-hydroxybutyl) 3,4-diazabicyclo [4.2.0]-oct-2-ene-5-one(isomer B;m.p. 133°-135°). The filtrate is further concentrated to give Isomer A (m.p. 115.5°-119° C).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[O-:28][C:29]#[N:30].[K+]>O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:29]([NH2:30])=[O:28])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 11 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.63 mmol) and acetic acid (108 μL, 1.89 mmol) in water (12 mL) was added portionwise potassium cyanate (153 mg, 1.89 mmol). After stirring overnight, the reaction mixture was quenched with a 0.1N aqueous solution of NaOH. The organic layer was separated and the aqueous layer extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) followed by DCM:MeOH (90:10) and DCM:MeOH:NH3 (90:5:5) to give the title compound (25 mg, 11%). 1H NMR (400 MHz, CDCl3) δ7.18 (d, 2H), 6.92-6.90 (d, 2H), 4.24 (s, 2H), 4.17 (t, 1H), 4.03 (t, 2H), 3.84-3.79 (m, 2H), 3.61-3.55 (m, 2H), 3.36-3.35 (d, 2H), 2.63 (t, 2H), 2.53 (m, 4H), 2.07-1.97 (m, 4H), 1.88-1.79 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[C:31]([O:35][CH3:36])=[N:32][C:33]=1[Cl:34].C(=O)([O-])[O-].[K+].[K+]>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>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=4[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[C:31]([O:35][CH3:36])=[N:32][C:33]=1[Cl:34]
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: COc1nc(Cl)c(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1nc(Cl)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 40 °C

Procedure:
A vial was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (From Step 1 in Example 73; 0.050 g, 0.122 mmol), (5,6-dichloro-2-methoxypyridin-3-yl)boronic acid (0.030 g, 0.134 mmol), potassium carbonate (0.051 g, 0.366 mmol), and Pd(Ph3P)4 (0.014 g, 0.012 mmol). The vial was flushed with Ar (g), then dioxane (0.915 ml) and water (0.305 ml) were added. The reaction was heated at 40° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-50% EtOAc:Heptane) to afford perfluorophenyl 1-(5,6-dichloro-2-methoxypyridin-3-yl)isoquinoline-6-sulfonate as a white solid. (ESI) 551.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][CH:15]1[CH2:20][CH2:19][Si:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(C2C=CC=CC=2)[CH2:17][CH2:16]1>>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][C@H:15]1[CH2:20][CH2:19][Si@H:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:17][CH2:16]1
Reactant: CCOc1ccc(O)c(F)c1F
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(OCC)c(F)c2F)CC1

Procedure:
The general procedure of Example 9 was repeated using 2,3-difluoro-4-ethoxyphenol and 4-bromomethyl-1-n-heptyl-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [NH2:1][N:2]1[C@H:6]([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][C:3]1=[O:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH2:7][C@H:6]1[N:2]([N:1]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[CH2:24][C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=2)[C:3](=[O:16])[CH2:4][CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(C(=O)Cc2ccc(F)cc2)n1
Reactant: NN1C(=O)CC[C@H]1COCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc(C(Cc2ccc(F)cc2)=NN2C(=O)CC[C@H]2COCc2ccccc2)n1

Procedure:
A mixture of (S)-1-amino-5-benzyloxymethyl-pyrrolidin-2-one (0.5 g, 2.27 mmol) and 2-(4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethanone (0.52 g, 2.27 mmol) in toluene (2.5 mL) in a round bottom flask equipped with a Dean-Stark apparatus is refluxed for 1 h. The mixture is concentrated in vacuo and the residue chromatographed on SiO2 (40% ethyl acetate/hexanes) to yield the title compound, 500 mg (52%), as a pale yellow oil.