Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:6][C:7]([C:9]1[C:23]2[CH:22]3[CH2:24][CH:18]([CH2:19][NH:20][CH2:21]3)[C:17]=2[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](Cl)=[N:14]2)=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH3:26][OH:27]>>[C:2]([O:6][C:7]([C:9]1[C:23]2[CH:22]3[CH2:24][CH:18]([CH2:19][NH:20][CH2:21]3)[C:17]=2[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([O:27][CH3:26])=[N:14]2)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c2c(cc3nc(Cl)ccc13)C1CNCC2C1
Reactant: CO
Agent: [Na]
Product: COc1ccc2c(C(=O)OC(C)(C)C)c3c(cc2n1)C1CNCC3C1

Procedure:
Sodium metal (˜12 mg) was dissolved in methanol (1 mL) under nitrogen with stirring and treated with a solution of 6-chloro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaen-10-carboxylic acid tert-butyl ester (118 mg, 0.33 mmol) in methanol (3 mL) and brought to reflux for 18 hours. The mixture was cooled, concentrated, treated with H2O and extracted with CH2Cl2. The organic layer was washed with saturated NaCl solution and filtered through a cotton plug then concentrated to an oil (165 mg). (TLC: 5% methanol/CH2Cl2 Rf 0.55).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]([C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)[CH:9]=[CH:10][N:11]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:8]3[CH:9]=[CH:10][N:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]3=[CH:14][N:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nccn2c(-c3ccc(F)cc3)ncc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nccn2c(-c3ccc(F)cc3)ncc12

Procedure:
To a solution of 3-(4-fluorophenyl)-imidazo[1,5-a]pyrazine-8-carboxylic acid ethyl ester (440.0 mg, 1.54 mmol) in methanol (10 mL) is added in several portions a solution of 85% KOH (330 mg, 4.9 mmol) in water (3 mL) (additional water is added to suspend the solid that precipitated) and the mixture is warmed at reflux. The methanol is removed in vacuo and the residue is diluted with water (15 mL) and made acidic (pH=4) with 1 N aqueous HCl. The solid is collected by filtration washing with water and then ether to afford 3-(4-fluorophenyl)-imidazo[1,5-a]pyrazine-8-carboxylic acid.
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.Br[C:50]1[N:55]=[CH:54][CH:53]=[CH:52][N:51]=1.C(N(C(C)C)CC)(C)C.C(O)(C)(C)C>O>[F:48][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:50]4[N:55]=[CH:54][CH:53]=[CH:52][N:51]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: Brc1ncccn1
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncccn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 86.8 %

Procedure:
To 1.21 g (1.79 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 0.90 g (5.7 mmol) of 2-bromopyrimidine, 1.0 ml (5.9 mmol) of diisopropylethylamine and 20 ml of tert-butanol were added, and the reaction solution was stirred at 65° C. for 2.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 1.17 g of the title compound as a white solid (yield: 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3ccc([N+](=O)[O-])cc32)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3ccc(N)cc32)CC1
Yield: 147.5 %

Procedure:
tert-Butyl 4-(6-nitro-1H-indazol-1-yl)piperidine-1-carboxylate (3.00 mmol, 1.04 g) and palladium (10% on C) (0.150 mmol, 0.160 g) in ethanol (30 mL) were stirred under a hydrogen atmosphere at 5 bar for 1 hour. The reaction mixture was filtered and concentrated at reduced pressure to afford the title compound (1.4 g). MS (ESI) m/z 317.2 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([F:19])[CH:10]=2)[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[CH:3]=1.[I:24](O)(=O)(=O)=O.II>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([F:19])[CH:10]=2)[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[I:24]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1cc(N)c(F)c(-c2ccc(C(F)(F)F)c(F)c2)n1
Agent: II
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(C(F)(F)F)c(F)c2)c(F)c(N)c1I
Temperature: 25 °C
Yield: 255.7 %

Procedure:
Methyl 4-amino-5-fluoro-6-(3-fluoro-4-(trifluoromethyl)phenyl)picolinate (500 mg, 1.51 mmol) was dissolved in CH3OH (0.6 mL) in a round bottom flask. Periodic acid (123 mg, 0.542 mmol) and iodine (306 mg, 1.204 mmol) were added, and the reaction mixture was heated at reflux with a drying tube for 12 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was dissolved in Et2O and washed with 10% sodium thiosulfate (Na2S2O3; 2×5 mL). The organic extracts were combined, dried over anhydrous Na2SO4, filtered, and concentrated providing methyl 4-amino-5-fluoro-6-(3-fluoro-4-(trifluoromethyl)phenyl)-3-iodopicolinate (635 mg, 92%): 1H NMR (400 MHz, DMSO-d6) δ 7.93 (dd, J=14.8, 6.8 Hz, 1H), 7.90-7.82 (m, 2H), 6.89 (s, 2H), 3.88 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −60.02 (t, J=12.4 Hz), −115.50 (td, J=12.2, 7.6 Hz), −139.91 (s); ESIMS m/z 459.62 ([M+H]+).
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:6]2[N:13](COCC3C=CC=CC=3)[CH:12]=[C:11]([CH2:23][N:24]([CH3:33])[C@H:25]([C@@H:28]([OH:32])[CH2:29][S:30][CH3:31])[CH2:26][OH:27])[C:7]=2[N:8]=[CH:9][N:10]=1.NN>[Pd].C(O)C>[NH2:4][C:5]1[C:6]2[NH:13][CH:12]=[C:11]([CH2:23][N:24]([CH3:33])[C@H:25]([C@@H:28]([OH:32])[CH2:29][S:30][CH3:31])[CH2:26][OH:27])[C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CSC[C@H](O)[C@H](CO)N(C)Cc1cn(COCc2ccccc2)c2c(N)ncnc12
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CSC[C@H](O)[C@H](CO)N(C)Cc1c[nH]c2c(N)ncnc12
Temperature: 25 °C
Yield: 82.8 %

Procedure:
Hydrazine hydrate (0.56 ml, 11.6 mmol) was added dropwise to a suspension of (2S,3R)-2-(((4-amino-5-(benzyloxymethyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)(methyl)amino)-4-(methylthio)butane-1,3-diol (50 mg, 116 μmol), palladium black (50 mg, 47.0 μmol) and ethanol (2 ml). Upon complete addition of the hydrazine the palladium went from a fine suspension to a granular form. The reaction was warmed to 60 C at which point TLC analysis indicated the reaction was complete therefore the reaction was cooled to ambient temperature, the palladium black removed by filtration and the filtrate concentrated in vacuo, and the crude residue co-distilled with ethanol and toluene (50 ml, 2:1 v/v). The resulting residue was purified by flash chromatography on silica gel eluting with 20% 7N NH3 in MeOH/DCM to afford (2S,3R)-2-(((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)(methyl)amino)-4-(methylthio)butane-1,3-diol (30 mg, 96 μmol, 83% yield) as a colourless syrup. 1H NMR (CD3OD) δ 8.16 (s, 1H), 7.43 (s, 1H), 4.11 (d, J=13.4 Hz, 1H), 3.86 (m, 3H), 3.73 (dd, J=11.5, 5.0 Hz, 1H), 2.88 (m, 1H), 2.77 (dd, J=13.7, 3.9 Hz, 1H), 2.54 (dd, J=13.6, 7.0 Hz, 1H), 2.43 (s, 3H), 2.07 (s, 3H). 13C NMR (CD3OD) 152.4, 151.0, 147.6, 129.8, 116.1, 115.4, 70.8, 67.2, 60.1, 50.3, 40.2, 38.8, 16.7.
Reaction SMILES: [I-].C[S+](C)(C)=O.[H-].[Na+].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[O:11].O1CCC[CH2:21]1.CS(C)=O>CS(C)=O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:10]2([CH3:21])[CH2:9][O:11]2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(C(C)=O)c1
Reactant: C1CCOC1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: COc1cccc(C2(C)CO2)c1
Temperature: 50 °C

Procedure:
Trimethyloxosulphonium iodide (100 g, 0.45 mole) was added as a slurry in dimethylsulphoxide (100 ml) to a stirred cooled suspension of sodium hydride (22.6 g of a 50% dispersion of oil, washed free from oil with ether) under nitrogen, keeping the internal temperature at 20° C. by ice-cooling. After stirring at room temperature for 1 hour 3-methoxyacetophenone (45 g, 0.3 mole) was added in a 1:1 mixtures of dry tetrahydrofuran-dimethylsulphoxide (100 ml). The reaction mixture was slowly heated to 50° C. over 1 hour and this temperature was maintained for 1 hour. The mixture was cooled, poured on to ice water and extracted with ether (4×150 ml). The combined extracts were washed with brine, dried (MgSO4) and evaporated to an oil (34.0 g) and used crude for the preparation of (3-methoxy)-α-methyl-α[(methylamino)methyl]benzene methanol.
Reaction SMILES: Cl.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1)[C:4]([NH2:6])=[NH:5].[NH:17]([C:21]1[S:22][CH:23]=[C:24]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]2[C:34](=O)[C:33](=[O:36])[C:32]=2[O:37]C)[N:25]=1)[C:18]([NH2:20])=[NH:19].C(N(CC)CC)C>CO>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:34]2[C:33](=[O:36])[C:32](=[O:37])[C:31]=2[NH:30][CH2:29][CH2:28][CH2:27][CH2:26][C:24]2[N:25]=[C:21]([NH:17][C:18]([NH2:20])=[NH:19])[S:22][CH:23]=2)[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: COc1c(NCCCCc2csc(NC(=N)N)n2)c(=O)c1=O
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N=C(N)Nc1nc(CCCCNc2c(NCCSCc3csc(NC(=N)N)n3)c(=O)c2=O)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
A mixture of 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole dihydrochloride (0.024 g), 1-[4-(2-guanidinothiazol-4-yl)butylamino]-2-methoxycyclobutene-3,4-dione (0.032 g) and triethylamine (0.03 ml) in dry methanol (1 ml) was stirred for 18 hours at room temperature. The white solid was filtered off, washed with methanol and dried in vacuo to give 1-[2-(2-guanidinothiazol-4-ylmethylthio)ethylamino]-2-[4-(2-guanidinothiazol-4-yl)butylamino]cyclobuten-3,4-dione, (0.022 g), m.p. 208°-210°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:15][CH:16]([NH2:18])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][CH:16]([CH3:17])[CH3:15])=[O:8])=[CH:9][CH:10]=1
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A solution of 4-bromobenzoic acid (4.00 g, 19.9 mmol, Aldrich: Cat. #108510) and thionyl chloride (10.0 mL, 137 mmol) was heated by microwave irradiation at 100° C. for 1 h, turning the heterogeneous solution to a homogeneous solution. The volatiles were removed in vacuo and the residue was azeotropically washed with dry acetonitrile several times (20 mL×4) to remove excess thionyl chloride. The residue was dissolved in anhydrous methylene chloride (40 mL) and cooled to 0° C. prior to the addition of 2-propanamine (8.0 mL, 94 mmol, 99.5% pure Aldrich [75-31-0]). After 1 hour, the reaction mixture was diluted with methylene chloride (20 mL) and quenched with H2O (5 mL). The layers were separated and the organic layer was washed with H2O (1×5 mL), saturated NaHCO3 (1×5 mL), H2O (1×5 mL), 1 N HCl (3×5 mL), H2O (1×5 mL), and brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the desired product (4.50 g, 93% yield) which was used directly in the next step without further purification. LCMS (M+H)+: m/z=242/244.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH:10]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:9]=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:9][CH:10]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13]1
Reactant: [H][H]
Reactant: CC1(C)CC(c2ccncc2N)=CC(N2C(=O)c3ccccc3C2=O)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccncc2N)CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 45 °C
Yield: 53 %

Procedure:
A solution of 2-(3-(3-aminopyridin-4-yl)-5,5-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (1.0 eq) in acetic acid (0.1 M) was purged with nitrogen for 10 min. Then 10% Pd/C (0.1 eq) was added. The reaction mixture was stirred at 45° C., 300 psi hydrogen atmosphere in a steel bomb overnight and at 65° C., 300 psi for 5 hours. Solids were removed by filtration over celite, then rinsed with EtOAc and MeOH. The filtrate was concentrated, diluted with EtOAc and washed 2× with sat. aq. 2M Na2CO3. Organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione (53%). LC/MS (m/z): MH+=350.3, Rt=0.78 min. The enantiomerically pure 2-((1R,5R)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione and 2-((1S,5S)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione were resolved by chiral HPLC (For analysis Rt=7.53 min and 13.11 min respectively; hexanes:ethanol=80:20 (v:v), Chiralcel OJ-H 100×4.6 mm at 1 mL/min. For preparative separation, hexanes:ethanol=80:20 (v:v), Chiralcel OJ-H 250×20 mm at 20 mL/min ). 1H NMR (CDCl3): δ 8.04 (s, 1H), 8.00 (d, 1H), 7.82 (m, 2H), 7.71 (m, 2H), 7.06 (d, 1H), 4.54 (m, 1H), 3.71 (m, 2H), 2.89 (m, 1H), 2.23-2.44 (m, 2H), 1.90 (m, 1H), 1.20-1.60 (m, 3H), 1.18 (s, 3H), 1.07 (s, 3H).
Reaction SMILES: C([O:8][C:9]([C@H:11]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14])=[O:10])C1C=CC=CC=1>CO.[Pd]>[Cl:18][C:17]([Cl:19])([Cl:20])[CH2:16][O:15][C:13]([CH2:12][C@@H:11]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:9]([OH:10])=[O:8])=[O:14]
Reactant: CCCCC[C@H](CC(=O)OCC(Cl)(Cl)Cl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCC[C@H](CC(=O)OCC(Cl)(Cl)Cl)C(=O)O
Yield: 94.1 %

Procedure:
2,2,2-Trichloroethyl 3-(R)-benzyloxycarbonyloctanoate (924 mg), prepared in Referential Example 8, was dissolved in methanol (8 ml) and was catalytically reduced by stirring the solution for 2 hours under an atmosphere of hydrogen in the presence of 10% palladium on charcoal (52 mg). After completion of the reaction, the catalyst was removed by celite filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography through silica gel using a 30:1 mixture of chloroform and methanol as an eluent, to give the desired compound (678 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12].[H][H]>[Pd].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[OH:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cc(Cl)cc(Cl)c1O
Temperature: 25 °C

Procedure:
A mixture of 10 g (0.048 moles) of 2,4-dichloro-6-nitrophenol and 0.2 g of 5% palladium on carbon slurried in 250 ml of glacial acetic acid was placed in a hydrogenation bottle. The bottle was stoppered under an atmosphere of 40 psi hydrogen and shaken at room temperature. The hydrogen was replenished during reaction. After four and one-half hours the hydrogen uptake was complete. The mixture then was filtered through a sintered glass funnel and the filtrate was stripped of solvent under reduced pressure. The yield of product was quantitative.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C(OC(=O)[NH:34][C:35]1[S:36][C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:38][N:39]=1)(C)(C)C>CC(N(C)C)=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>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:37]4[S:36][C:35]([NH2:34])=[N:39][CH:38]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)s4)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 36.4 %

Procedure:
A suspension of 2-chloro-6-(4-methanesulphonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (201 mg, 0.465 mmol), (5-tributylstannyl-thiazol-2-yl)-carbamic acid tert-butyl ester (341 mg, 0.7 mmol), and Pd(PPh3)4 (27 mg, 0.023 mmol) in anhydrous DMA was heated in a microwave at 150° C. for 10 mins. Ethyl acetate/water extraction and purification on silica using 10% methanol in ethyl acetate as the eluent to give 5-[6-(4-methanesulphonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-thiazol-2-ylamine as an off-white solid (84 mg, 36%).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:16][C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[O:9][CH2:8]1)(=O)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:18]1([CH2:17][NH:24][CH2:6][C@@H:7]2[O:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[O:9][CH2:8]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OC[C@@H]1COc2cccnc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(CNC[C@H]2COc3cccnc3O2)cc1

Procedure:
A mixture of intermediate (3) (0.041 mol), benzylamine (0.041 mol) and NaHCO3 (0.11 mol) in dioxane (100 ml) was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was taken up in water and DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The desired fractions were collected, the solvent was evaporated, yielding (S)-2,3-dihydro-N-(phenylmethyl)-[1,4]dioxino[2,3-b]pyridine-3-methanamine (intermediate 55).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH2:31]([NH:33][S:34](Cl)(=[O:36])=[O:35])[CH3:32]>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([O:11][S:34](=[O:36])(=[O:35])[NH:33][CH2:31][CH3:32])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Reactant: CCNS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCNS(=O)(=O)Oc1cc(C(C)(C)C)c(SS(=O)(=O)c2ccc(C)cc2)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer and nitrogen were added toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR; 6.86 g, 19.6 mmol), Et2O (100 mL), and NEt3 (3.25 mL, 23.4 mmol), respectively. The solution was cooled to 0° C. and treated rapidly with a solution of (ethyl amino)sulfonyl chloride (3.37 g, 23.4 mmol) in Et2O (10 mL). The reaction was stirred for 30 minutes and then filtered. The solids were washed with Et2O, and the filtrate was concentrated. The resulting residue was dried in a high vacuum oven at 40° C. overnight to yield the title compound. 1H NMR (CDCl3) δ 1.15 (s, 9 H), 1.23 (t, 3 H) 2.19 (s, 3 H), 2.35 (s, 3 H), 3.30 (m, 2 H), 4.75 (br t, 1 H), 7.16 (s, 1 H), 7.19 (s, 1 H), 7.32 (d, 2 H), 7.39 (d, 2 H).
Reaction SMILES: [Br:1]Br.[CH3:3][CH2:4][C:5]([C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[F:17])=[O:6]>ClCCl>[Br:1][CH:4]([CH3:3])[C:5]([C:7]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:8]=1[F:17])=[O:6]
Reactant: CCC(=O)c1cc(C(F)(F)F)ccc1F
Reactant: BrBr
Solvent: ClCCl
Product: CC(Br)C(=O)c1cc(C(F)(F)F)ccc1F
Yield: 99.5 %

Procedure:
Slowly add a solution of bromine (3.34 g, 0.95 equiv) in dichloromethane (80.00 mL) to a solution of 2-fluoro-5-(trifluoromethyl)propiophenone (5 g, 22.03 mmol) in dichloromethane (80 mL) is with stirring so that the brown color of bromine just disappears. Wash the reaction mixture with saturated NaHCO3, dry over Na2SO4 and concentrate to provide 6.22 g of crude material.
Reaction SMILES: C(=O)=[N:2][S:3](Cl)(=[O:5])=[O:4].[CH:8]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([CH:20]([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH:14]=[O:15])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[S:3](=[O:4])(=[O:5])([O:19][C:18]1[C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[CH:8]([CH3:10])[CH3:9])[NH2:2]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C=O)cc(C(C)C)c1OS(N)(=O)=O
Temperature: 25 °C
Yield: 33.1 %

Procedure:
N-Chlorosulfonyl isocyanate (21.6 mL, 248 mmol) was added slowly to a warm solution of 3,5-diisopropyl-4-hydroxy-benzaldehyde (24.4 g, 118 mmol) in 500 mL toluene. The resulting solution was heated to reflux for 4 hours and then cooled to room temperature and concentrated to give a brown oil. Quenched with 200 g ice and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate, filtered, and concentrated to give a tan solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 11.15 g of the title compound as an off-white solid.
Reaction SMILES: [Na].[N:2]1([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[N:3]1.[CH2:12]([OH:14])[CH3:13]>>[N:2]1([C:7]2([C:10](=[NH:11])[O:14][CH2:12][CH3:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[N:3]1
Reactant: N#CC1(n2cccn2)CC1
Reactant: CCO
Agent: [Na]
Product: CCOC(=N)C1(n2cccn2)CC1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Sodium metal (12 mg, 0.52 mmol) was added to anhydrous ethanol (3 mL) at room temperature and the mixture was stirred for 15 min. 1-(1H-pyrazol-1-yl)cyclopropanecarbonitrile (0.1 g, 0.75 mmol) dissolved in ethanol (2 mL) was added and the reaction mixture was heated to 70° C. for 90 min. The resulting solution was used without further purification.