Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].[C:16](=O)([O:18]CC)[NH2:17]>[Cl-].[Zn+2].[Cl-]>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[NH:1][C:16](=[O:18])[N:17]=1
Reactant: Nc1sccc1C(=O)c1ccccc1Cl
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: O=c1nc(-c2ccccc2Cl)c2ccsc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 10.0 g of 2-amino-3-(o-chlorobenzoyl)thiophene, 14.26 g of ethyl carbamate and 0.86 g of zinc chloride is heated at 200°C for 30 minutes. After cooling, the reaction mixture is well washed with chloroform, then with water, and filtered to give crude crystals of 4-(o-chlorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:5][CH2:6]1)=[O:36]
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OCC(=O)Cl
Product: O=C(NCC1CCN(C(=O)CO)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([N:24]4[C:36]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:30]5[C:25]4=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:23]=3)[C:17]([O:19]C)=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C1COCC1.CO.O>[CH:10]1[C:11]2[N:12]([C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([N:24]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=5[C:31]5[C:36]4=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:23]=3)[C:17]([OH:19])=[O:18])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Reaction time: 4.5 h

Procedure:
To a solution of methyl 3,5-di(carbazol-9-yl)benzoate (1.0 g, 2.14 mmol) in THF/methanol (25.0 ml, 15:10) was added KOH (0.6 g, 10.69 mmol) in water (2.0 ml) at room temperature under stirring. The reaction was carried out at room temperature for 4.5 hours. The THF was evaporated. Next, methanol (20.0 ml) was added and then HCl water solution (80.0 ml; 15.0 ml of 36-38% HCl in 65.0 ml of water) was added. The mixture was stirred for 1 hour and a pale yellow solid product was obtained by filtration. The product was purified by recrystallization from acetone/water: 0.95 g (97.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]2[NH:8][C:9]([S:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:21])[CH3:20])=[O:12])=[N:10][C:6]=2[CH:5]=1)([O-])=O>C(O)C.O=[Pt]=O>[NH2:1][C:4]1[CH:23]=[CH:22][C:7]2[NH:8][C:9]([S:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]([CH3:20])[CH3:21])=[O:12])=[N:10][C:6]=2[CH:5]=1
Reactant: CN(C)c1ccccc1S(=O)c1nc2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=[Pt]=O
Solvent: CCO
Product: CN(C)c1ccccc1S(=O)c1nc2cc(N)ccc2[nH]1
Reaction time: 72 h

Procedure:
2-(5-Nitro-1H-benzimidazol-2-yl sulphinyl)-N,N-dimethylbenzenamine (3 g) was suspended in ethanol (300 ml), and hydrogenated at 1 atmosphere at room temperature, using platinium oxide as catalyst, for 3 days.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[CH:3]=1.CN(C=O)C.I[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=1.O>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=2)[CH:3]=1
Reactant: C#Cc1cccc(Br)c1
Reactant: FC(F)Oc1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)Oc1ccc(C#Cc2cccc(Br)c2)cc1
Reaction time: 4 h

Procedure:
To a mixture of 1-bromo-3-ethynylbenzene (9.1 g, 50.26 mmol), TEA (22.38 g, 30.8 mL, 221.1 mmol), PdCl2(ACN)2 (1.41 g, 2.01 mmol) and DMF (60 mL) was added 4-iodo(difluoromethoxy)benzene (10.85 g, 40.21 mmol). The reaction mixture became warm after the addition was completed. The mixture was stirred for 4 h. Then it was poured into water and diluted with EtOAc. The aqueous layer was separated and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated onto 40 g Celite. Flash chromatography (SiO2, Hexanes) provided 12 g, 92%, of the title compound as a yellow oil that crystallized into a yellow solid upon standing.
Reaction SMILES: [CH2:1]([C@@:4]1([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:12]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:11][CH:6](OC(=O)C)[C@@H:5]1[O:22][C:23](=[O:25])[CH3:24])[CH:2]=[CH2:3].[NH:34]1[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]1=[O:36].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[C:23]([O:22][C@@H:5]1[C@:4]([CH2:1][CH:2]=[CH2:3])([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:12]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:11][C@H:6]1[N:34]1[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]1=[O:36])(=[O:25])[CH3:24]
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)OC(OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: CC#N
Product: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
To a stirred solution of the anomeric mixture 0C (β:α˜2:1, 11.8 g, 26.0 mmol) (P. Nielsen, H. M. Pfundheller and J. Wengel, Chem. Commun., 1997, 825; P. Nielsen, H. M. Pfundheller, C. E. Olsen and J. Wengel, J. Chem. Soc., Perkin Trans. 1, 1997, in the press) and thymine (6.55 g, 52.0 mmol) in anhydrous acetonitrile (250 cm3) was added N,O-bis(trimethylsilyl)acetamide (44.9 cm3, 182 mmol). The reaction mixture was stirred at reflux for 1 h and cooled to 0° C. Trimethylsilyl triflate (8.00 cm3, 44.0 mmol) was added dropwise and the solution was stirred at room temperature for 12 h. An ice-cold saturated aqueous solution of sodium hydrogencarbonate (270 cm3) was added and the mixture was extracted with dichloromethane (3×125 cm3). The organic phase was washed with saturated aqueous solutions of sodium hydrogen-carbonate (2×125 cm3) and brine (2×125 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 1 as a white solid material (11.6 g, 86%). δH (CDCl3) 8.64 (1 H, br s, NH), 7.75 (1 H, d, J 1.1, 6-H), 7.41-7.25 (10 H, m, Bn), 6.43 (1 H, d, J 8.2, 1′-H), 5.88 (1H, m, 2″-H), 5.66 (1 H, d, J 8.2, 2′-H), 5.12 (1 H, s, 3″-Ha), 5.07 (1 H, dd, J 1.5, 8.5, 3″-Hb), 4.85 (1H, d, J 11.2, Bn), 4.64 (2H, s, Bn), 4.63 (1 H, d, J 11.2, Bn), 4.33 (1 H, br s, 4′-H), 3.81 (1 H, dd, J 2.7, 11.1, 5′-Ha), 3.65 (1 H, m, 5′-Hb), 2.81-2.65 (2 H, m, 1″-Ha, 1″-Hb), 2.08 (3 H, s, COCH3), 1.52 (3H, d, J 0.8, CH3). δC (CDCl3) 170.1 (C═O), 163.6 (C-4), 150.9 (C-2), 138.1, 136.6 (Bn), 136.0 (C-6), 131.6 (C-2″), 128.8, 128.4, 128.3, 127.6, 127.5, 127.1 (Bn), 118.5 (C-3″), 111.1 (C-5), 84.2, 83.4, 83.1, 77.4 (C-1′, C-2′, C-3′, C-4′), 73.6, 69.2 (Bn), 65.6 (C-5′), 33.7 (C-1″), 20.8 (COCH3), 11.9 (CH3) (Found: C, 66.8; H, 6.3; N, 5.1. C29H32N2O7 requires C, 66.9; H, 6.2; N, 5.4%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[N:16]1[CH2:47][CH2:46][C:19]2([N:24]([CH2:25][C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[CH:28]=[CH:29][N:30]4S(C3C=CC(C)=CC=3)(=O)=O)[C:23](=[O:45])[CH2:22][CH2:21][CH2:20]2)[CH2:18][CH2:17]1>CO>[NH:30]1[C:31]2[C:27](=[C:26]([CH2:25][N:24]3[C:19]4([CH2:18][CH2:17][N:16]([C:8]5[O:7][C:11]6[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=6[N:9]=5)[CH2:47][CH2:46]4)[CH2:20][CH2:21][CH2:22][C:23]3=[O:45])[CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCN(c4nc6ccccc6o4)CC5)cccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: O=C1CCCC2(CCN(c3nc4ccccc4o3)CC2)N1Cc1cccc2[nH]ccc12
Reaction time: 18 h
Yield: 69.1 %

Procedure:
Cs2CO3 (430 mg, 1.32 mmol) was added to a stirred solution of 9-(benzo[d]oxazol-2-yl)-1-((1-tosyl-1H-indol-4-yl)methyl)-1,9-diazaspiro[5.5]undecan-2-one (250 mg, 0.44 mmol) in methanol (10 mL) and stirring was continued for 18 h at 78° C. The reaction mixture was concentrated, water was added to the residue and extracted with ethyl acetate (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by reversed phase HPLC (column Zorbax eclipseXDB C18 21.2×150 mm 5 ♀m, flow 20 mL/min, eluent: gradient water/acetonitrile) to yield the title compound (126 mg, 69%). [1H NMR (400 MHz, CDCl3) ♀ ppm 8.30 (br s, 1H), 7.36-6.96 (m, 7H), 6.78 (d, 1H), 6.46 (m, 1H), 4.95 (s, 2H), 4.16 (dd, 2H), 3.18 (t, 2H), 2.65 (t, 2H), 2.20-2.05 (m, 4H), 1.95-1.88 (m, 2H), 1.75-1.61 (m, 2H); LCMS RtE=1.32 min, [M+H]+=415.1].
Reaction SMILES: [F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:16]4[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=4)=[CH:11][CH:12]=3)[C:7]3([N:27]=[C:26]([NH2:28])[CH2:25][O:24][CH2:23]3)[C:6]=2[CH:5]=[C:4]([O:29]C)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:28][C:26]1[CH2:25][O:24][CH2:23][C:7]2([C:6]3[CH:5]=[C:4]([OH:29])[CH:3]=[C:2]([F:1])[C:15]=3[O:14][C:13]3[C:8]2=[CH:9][C:10]([C:16]2[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:12]=3)[N:27]=1
Reactant: COc1cc(F)c2c(c1)C1(COCC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC1=NC2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(O)cc12
Reaction time: 45 h
Yield: 95.1 %

Procedure:
To a suspension of 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (1.668 g, 4.07 mmol) in DCM (12 ml) was added boron tribromide (0.963 mL, 10.19 mmol). Stirring was continued for 45 hrs at 0° C. at which point the mixture was removed from the bath and stirred for 2 hrs at RT. The reaction mixture was recooled to 0° C. and quenched by careful addition of saturated aqueous NaHCO3 solution (˜10 mL). The mixture became colorless with a white precipitate. The solvent was removed in vacuo, the mixture was diluted with water and filtered. The solid was washed with water and dried on air for 2 hrs, then for 2 hrs in high vacuum at RT to afford 5-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-2′-ol (1.53 g, 3.87 mmol, 95% yield).
Reaction SMILES: [C:1]1([N:7]2[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH2:9][C:8]2=[O:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48]>O1CCCC1>[C:1]1([N:7]2[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:31])([CH3:33])[CH3:32])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:10][CH:9]([CH2:46][C:47]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:48])[C:8]2=[O:34])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](OCCC1=CCC(=O)N(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC1=CC(CC(=O)OCc2ccccc2)C(=O)N(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 45.5 %

Procedure:
Compound (9) (650 mg, 1.38 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to -78° C. The resulting reaction mixture was treated with 1.8 mL of a 1M solution of lithium bis (trimethylsilyl)amide in tetrahydrofuran and stirred for 20 min. At this time, benzyl 2-bromoacetate (437 μL, 2.76 mmol) was added, the reaction continued at -78° C. for 10 rain and then warmed to room temperature (removed dry ice/isopropanol bath). After the reaction mixture reached room temperature, 10% NH4Cl (aqueous) was added and the resulting mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous MgSO4, filtered and evaporated at reduced pressure. The residue was purified using flash chromatography (silica gel, 4×20 cm, 20- 40% ethyl acetate/hexane) to yield the title compound (11) (388 mg, 46%). Compound (21): 1H NMR (CDCl3) δ 1.05 (9H, s), 1.98-2.73 (5H, m), 2.90-3.23 (1H, m), 3.37-3.73 (1H, m), 3.77 (2H, t, J=6.8 Hz), 4.07-4.80 (2H, m), 5.03-5.27 (3H, m), 6.97-7.83 (20H, m); MS (DCI/NH4) m/e 618 (M+H)+ ; TLC Rf 0.47 (silica gel, 7:3 hexane:ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)CCO.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: OCC1CCNCC1
Agent: [Cu]I
Agent: CN(C)CCO
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: OCC1CCN(c2ccc(Br)cc2)CC1
Temperature: 55 °C

Procedure:
A mixture of 1-bromo-4-iodo-benzene (2.5 g, 8.8 mmol), piperidine-4-yl-methanol (2.0 g, 17.7 mmol), potassium phosphate (3.8 g, 17.7 mmol) and copper (I) iodide (3.8 g, 17.7 mmol) in N,N-dimethyl ethanolamine (8.4 mL) was heated to 55° C. for 48 hours. The mixture was allowed to cool to ambient temperature, water was added and the mixture was extracted with ether 2×. The combined organic extracts were washed with water 3×. The organic extract was dried over magnesium sulfate, filtered and concentrated to a crude residue. The residue was dissolved in methylene chloride and passed through a silica gel pad. The pad was eluted ethyl acetate/heptanes (3:7) to ethyl acetate/heptanes (6:4) and the filtrate was concentrated in vacuo to afford [1-(4-bromo-phenyl)-piperidin-4-yl]-methanol as a white solid. (2.4 g)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:16][CH3:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH:15]([CH2:16][CH3:17])[CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:24][CH:23]=1
Reactant: CCC(CN1CCN(Cc2ccccc2)CC1)Oc1ccc(F)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: CCC(CN1CCNCC1)Oc1ccc(F)cc1
Reaction time: 2 h
Yield: 31.8 %

Procedure:
1-Benzyl-4-[2-(4-fluorophenoxy)butyl]piperazine 717 mg was dissolved in dichloroethane 10 ml, and 1-chloroethyl chloroformate 598 mg was added thereto, and the mixture was stirred for 2 hours under reflux with heating. After the reaction mixture was concentrated, methanol 10 ml was added thereto, and the mixture was stirred for 1 hour under reflux with heating. After the mixture was evaporated, it was partitioned by adding ether and 2N hydrochloric acid, and the aqueous layer was neutralized with 2N sodium hydroxide followed by extracting with ethyl acetate. The organic layer was washed with water and brine successively, dried over magnesium sulfate anhydride and evaporated, whereby the title compound 168 mg, 32% was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[O:29][C:30]6[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=6[N:32]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5nc6ccccc6o5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-chloro-benzoxazole following a procedure analogous to that described for Intermediate 12; K2CO3 and acetonitrile are used as base and solvent, respectively, at room temperature. LC (method 4): tR=0.83 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[N:22]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:10]([CH3:29])[CH:9]=1)=[O:6].[CH3:33][N:34]([CH3:38])[CH2:35][C:36]#[CH:37]>C(N(CC)CC)C.C(#N)C.ClCCl.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:33][N:34]([CH3:38])[CH2:35][C:36]#[C:37][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[N:22]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:10]([CH3:29])[CH:9]=1)=[O:6]
Reactant: C#CCN(C)C
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(I)c3)cc2C)n1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(C#CCN(C)C)c3)cc2C)n1
Reaction time: 3.5 h

Procedure:
A mixture of 3-iodo-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide (0.20 g, 0.37 mmol), N,N-dimethylprop-2-yn-1-amine (0.080 mL, 0.74 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.013 g, 0.020 mmol), copper (I) iodide (0.0035 g, 0.020 mmol) in triethylamine (1.5 mL) and acetonitrile (5 mL) was heated in a sealed tube to 100 deg. C. for 3.5 h. The reaction was diluted in dichloromethane and filtered. The filtrate was concentrated in vacuo and the resulting material was purified by silica gel chromatography using MeOH/dichloromethane as eluent to give 3-(3-(dimethylamino)prop-1-ynyl)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide as a brown solid. MS m/z=493 [M+1]+. Calc'd for C29H28N6O2: 492.58.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)[CH2:3]1.[CH3:22][CH:23]([NH2:25])[CH3:24].CCN(C(C)C)C(C)C>>[OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:25][CH:23]([CH3:24])[CH3:22])[N:11]=2)[CH2:3]1
Reactant: CC(C)N
Reactant: C[C@@H]1CC[C@@H](Nc2nc(S(C)(=O)=O)ncc2C#N)C[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1ncc(C#N)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To the solution of 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (446 mg, 1.437 mmol) from the previous step was added propan-2-amine (0.367 mL, 4.31 mmol) and DIEA (1.004 mL, 5.75 mmol). The reaction was stirred at 80° C. for 4 h and then allowed to cool to ambient temperature. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (0-90% ethyl acetate in hexanes) to afford 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(isopropylamino)pyrimidine-5-carbonitrile (381 mg, 1.317 mmol, 92% yield). MS (ESI) m/z 290.2 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:18][CH2:19][C:20]([CH3:26])([OH:25])[C:21]([F:24])([F:23])[F:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>CN1C(=O)CCC1.CCOC(C)=O.O>[F:22][C:21]([F:24])([F:23])[C:20]([OH:25])([CH3:26])[CH2:19][NH:18][C:14]([C:3]1[C:2]([NH2:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([O:12][CH3:13])[N:4]=1)=[O:16]
Reactant: CC(O)(CN)C(F)(F)F
Reactant: COc1nc(C(=O)O)c(N)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1nc(C(=O)NCC(C)(O)C(F)(F)F)c(N)cc1C(F)(F)F

Procedure:
A solution comprising 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D)(4 g, 16.94 mmol) and 3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (Intermediate R) (3.04 g, 16.94 mmol) in NMP (188 ml) was treated with HATU (7.73 g, 20.33 mmol) followed by dropwise addition (2 ml portions) of DIPEA (8.88 ml, 50.8 mmol) over 1 hour. After stirring for a further hour, the reaction mixture was poured into water (450 ml) and EtOAc (450 ml). The aqueous phase was acidified with 5M HCl (50 ml) and the layers were separated. The organic portion was washed with 2M NaOH (200 ml), water (4×200 ml), brine (2×100 ml), dried over MgSO4, filtered and concentrated in vacuo to afford a brown solid. Purification of the solid by chromatography on silica (220 g pre-packed silica cartridge) eluting with 0-50% EtOAc in iso-hexane afforded the racemate, 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (Ex. 4) as a yellow solid;
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[C:21]([NH:28][CH2:29][C:30]#[CH:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[C:24]([O:23][C:21](=[O:22])[NH:28][CH2:29][C:30]#[C:31][C:13]1[CH:12]=[N:11][C:7]2[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]3[C:2]([Cl:1])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:20])[C:6]=2[CH:14]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Clc1cccc(Cl)c1CN1CCNc2ncc(I)cc21
Reactant: C#CCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1cnc2c(c1)N(Cc1c(Cl)cccc1Cl)CCN2

Procedure:
1-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (1.951 g) was coupled with N-boc propargylamine as in General Procedure 5 to give the title compound as an orange solid. LCMS: m/z=447.53 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.40 (9H, s), 2.86 (2H, m), 3.27 (2H, m), 3.95 (2H, d, J=5.6 Hz), 4.46 (2H, s), 6.86 (1H, s), 6.89 (1H, s), 7.29 (1H, m), 7.42 (2H, m), 7.54 (2H, d, J=8.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:17][CH:18]=3)[N:10]=2)[CH:7]=1
Reactant: O=Cc1ccc(-c2nc3ccc(Br)cn3c2-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-c2nc3ccc(Br)cn3c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the stirred solution 4-(6-bromo-3-phenylimidazo[1,2-a]pyridin-2-yl)benzaldehyde (0.795 mM) in 15 mL of methanol is added NaBH4 (1.5 eq) at 0° C. and the reaction is allowed to stir at room temperature for 1 hr. The reaction is concentrated and quenched with water. The precipitated solid is filtered and dried to yield the desired product.