Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: 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+].[Cl:53][C:54]1[CH:63]=[C:62]2[C:57]([C:58]([NH:64][C@H:65]3[CH2:70][CH2:69][C@@H:68]([NH:71]C4C5C(=CC(Cl)=CC=5)N=CC=4)[CH2:67][CH2:66]3)=[CH:59][CH:60]=[N:61]2)=[CH:56][CH:55]=1.[Br:83][C:84]1[C:85](Br)=[C:86]([CH3:90])[CH:87]=[CH:88][CH:89]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:83][C:84]1[CH:89]=[C:88]([NH:71][CH:68]2[CH2:67][CH2:66][CH:65]([NH:64][C:58]3[C:57]4[C:62](=[CH:63][C:54]([Cl:53])=[CH:55][CH:56]=4)[N:61]=[CH:60][CH:59]=3)[CH2:70][CH2:69]2)[CH:87]=[C:86]([CH3:90])[CH:85]=1
Reactant: Cc1cccc(Br)c1Br
Reactant: Clc1ccc2c(N[C@H]3CC[C@@H](Nc4ccnc5cc(Cl)ccc45)CC3)ccnc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc(NC2CCC(Nc3ccnc4cc(Cl)ccc34)CC2)c1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 16 %

Procedure:
A dry 250 mL 3-necked flask was charged with Pd2(dba)3 (266 mg, 2 mol %), BINAP, 384 mg, 4 mol %), and sodium t-butoxide (2.2 g, 0.023 mol) in 50 mL dry toluene. After 5 minutes, 23A cis-N,N′-bis(7-chloroquinolin-4-yl)cyclohexane-1,4-diamine (4.00 g, 0.0145 mol) was added in one portion followed by dibromotoluene (3.6 g, 0.0145 mol). The solution was heated at 70° C. under nitrogen overnight. The contents were filtered, concentrated and the residue was purified by flash chromatography (5% methanol in dichloromethane) to provide 1.03 g, a 16% yield. MS (ESI(+)Q1MS m/z 445 (M+2 H)+; 1 H NMR (300 MHz, MeOH) δ ppm 8.51 (d, 1 H), 8.37 (d, 1 H), 7.86 (d, 1 H), 7.69 (dd, 1 H), 6.96 (d, 1 H), 6.66 (s, 1 H), 6.61 (s, 1 H), 6.49 (s, 1 H), 3.98 (m, 1 H), 3.63 (m, 1 H), 2.22 (s, 3 H), 1.85-2.01 (m, 8 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.CS[C:21]1[S:22][CH2:23][CH2:24][N:25]=1>COCCO>[S:22]1[CH2:23][CH2:24][N:25]=[C:21]1[NH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CSC1=NCCS1
Reactant: CC(=O)Nc1nc(/C=C/c2ccc(N)cc2)cs1
Solvent: COCCO
Product: CC(=O)Nc1nc(/C=C/c2ccc(NC3=NCCS3)cc2)cs1
Temperature: 120 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A mixture of N-{4-[(E)-2-(4-aminophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (200 mg), 2-(methylsulfanyl)-4,5-dihydro-1,3-thiazole (103 mg), hydrochrolic acid (0.064 ml) and 2-methoxyethanol (2 ml) was stirred at 120° C. for 8 hours. The reaction mixture was concentrated in vacuo. The residue was purified by silica-gel flash column chromatography with hexane:ethyl acetate (3:1) as an eluent. The crystalline residue was collected and washed with ethyl acetate to give N-(4-{(E)-2-[4-(4,5-dihydro-1,3-thiazol-2-ylamino)phenyl]ethenyl}-1,3-thiazol-2-yl)acetamide (150 mg).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[NH:19][CH2:18][CH:17]=[C:11]4[NH:12][C:13](=[O:16])[C:14]=2[C:10]=34)=[C:5]([CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:4]=[CH:3]1.[C:25](Cl)(=[O:28])[O:26][CH3:27].C(N(C(C)C)C(C)C)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.CO>[CH3:1][N:2]1[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[N:19]([C:25]([O:26][CH3:27])=[O:28])[CH2:18][CH:17]=[C:11]4[NH:12][C:13](=[O:16])[C:14]=2[C:10]=34)=[C:5]([CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:4]=[CH:3]1
Reactant: CN1C=CC(CS(C)(=O)=O)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COC(=O)N1CC=c2[nH]c(=O)c3c4c(ccc1c2-3)=C(CS(C)(=O)=O)C=CN4C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
A mixture of Example 6a (0.0145 g, 0.042 mmol) in N,N-dimethylacetamide (0.5 mL) was treated sequentially with methyl carbonochloridate (0.016 mL, 0.211 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.074 mL, 0.422 mmol) and stirred overnight at ambient temperature. The reaction mixture was then diluted with methanol (1.2 mL), treated with sodium carbonate (0.011 g, 0.105 mmol) and stirred at ambient temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate and water and washed with saturated aqueous sodium chloride. The aqueous layers were combined and exhaustedly extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC(C18, acetonitrile/water (0.1% TFA), 0-50%) to provide 0.0069 g (40.7%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.76 (d, J=1.53 Hz, 1H), 7.69 (s, 1H), 7.29 (m, 1H), 7.23 (m, 1H), 6.79 (s, 1H), 5.00 (d, J=15.56 Hz, 1H), 4.44 (m, 2H), 4.12 (s, 3H), 3.94 (d, J=15.26 Hz, 1H), 3.50 (s, 3H), 2.93 (s, 3H). MS (ESI+) m/z 402.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:38]>C(O)C>[ClH:38].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[C:20]([C:33]([F:36])([F:34])[F:35])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccs3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cccs2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 46-4 (740 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by HPLC, the obtained residue was converted to hydrochloride by adding hydrogen chloride containing ether (1 mol/l, 15 ml), and the precipitate was collected by filtration and dried to give the object product (360 mg) as a white powder.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C([NH+](CCCCCCCC)CCCCCCCC)CCCCCCC.S(OC)(O)(=O)=[O:39].NCP(=O)(O)O>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].OO>[O:39]1[CH:4]2[CH:3]1[CH2:2][CH:1]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH2:6][CH2:5]2
Reactant: COS(=O)(=O)O
Reactant: C=CCOC(=O)C1CC=CCC1
Agent: O=[W](=O)([O-])[O-]
Agent: CCCCCCCC[NH+](CCCCCCCC)CCCCCCCC
Agent: NCP(=O)(O)O
Solvent: O
Product: C=CCOC(=O)C1CCC2OC2C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 8714.1 %

Procedure:
A three neck flask of 500 mL equipped with a reflux condenser, a thermometer, a stirring device, a dropping funnel and an oil bath was charged with 100.0 g of allyl 3-cyclohexene-1-carboxylate, 2.34 g of methyl hydrogensulfate trioctylammonium, 3.96 g of sodium tungstate dihydrate and 0.45 g of aminomethylphosphonic acid. The flask was heated on the oil bath maintained at 90° C., and 80 ml of 30% aqueous hydrogen peroxide was dropwise added thereto through the dropping funnel in 180 minutes to ripen the solution as it was for 4 hours. The flask was cooled on an ice bath, and surplus hydrogen peroxide was removed by 300 ml of a saturated sodium thiosulfate aqueous solution. Then, the solution was extracted twice with 200 ml of ethyl acetate. The ethyl acetate solution thus obtained was dried on anhydrous sodium sulfate for a night, and ethyl acetate which was the solvent was removed by means of a rotary evaporator. Then, the residue was refined by a silica gel chromatography filled with 25% hydrous silica gel to obtain 79.6 g of allyl 3,4-epoxycyclohexane-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[CH:32](O)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:27][CH2:28][N:29]([CH:32]=[O:33])[CH2:30][CH2:31]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: O=CO
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCN(C=O)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (8.0 mg, 0.0174 mmol), formic acid (1.3 μL, 0.0349 mmol), TBTU (11.2 mg, 0.0349 mmol), DIPEA (20 μL, 0.09 mmol) and DCM (1 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=7.1 Hz, 3 H), 1.90-2.07 (m, 2 H), 2.10-2.23 (m, 2 H), 2.90 (td, J=12.9, 2.9 Hz, 1 H), 3.32-3.37 (m, 1 H), 3.89 (ddd, J=13.5, 2.2, 2.0 Hz, 1 H), 4.41-4.56 (m, 2 H), 5.28 (q, J=7.2 Hz, 1 H), 7.18 (t, J=8.6 Hz, 1 H), 7.30-7.53 (m, 3 H), 7.58 (s, 1 H), 7.90 (s, 1 H), 8.07 (s, 1 H), 8.31 (d, J=1.8 Hz, 1H). MS (ES+): m/z 486.00 (100) [MH+]. HPLC: tR=3.30 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.Br[CH:20]1[CH2:23][CH2:22][CH2:21]1.[I-].[Na+]>CN(C=O)C>[CH:20]1([S:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)(=[O:11])=[O:10])[CH2:23][CH2:22][CH2:21]1
Reactant: BrC1CCC1
Reactant: O=S(O)c1ccc(F)c(F)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(F)c(F)c1)C1CCC1
Temperature: 100 °C

Procedure:
To 5.6 mmol 3,4-difluoro-benzenesulfinic acid and 6.2 mmol triethylamine in 10 ml DMF were added 8.4 mmol bromocyclobutane and 0.2 mmol sodium iodide and the mixture heated at 100° C. for 48 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 233.1 (M+H+, 100%)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH2:37][CH3:38])=[CH:34][C:35]=2[CH3:36])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:39])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[C:35]([CH3:36])[CH:34]=1)[CH3:38]
Reactant: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C)c(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-ethyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M234) (156 mg, 0.28 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (73 mg, 60%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:54][C@H:55]([CH2:59][CH3:60])[CH2:56][C:57]#[N:58]>CN(C=O)C>[C:57]([CH2:56][C@H:55]([NH:54][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([N:12]2[C:13]([OH:14])=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH:10]=[N:11]2)=[N:16][CH:17]=1)[CH2:59][CH3:60])#[N:58]
Reactant: CC[C@@H](N)CC#N
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](CC#N)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (29 mg, 0.095 mmol), EDCI (27.2 mg, 0.142 mmol), HOBT (19.2 mg, 0.142 mmol) in DMF (1 mL) and added N,N-diisopropyl ethylamine (66.0 μL, 0.379 mmol). Then (R)-3-aminopentanenitrile (13.9 mg, 0.142 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using a gradient of 40-65% ACN (with 0.035% TFA) in water (with 0.05% TFA) to give the title compound (16.2 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3H) 1.67 (quin, J=7.20 Hz, 2H) 2.70-2.95 (m, 2H) 4.05-4.22 (m, 1H) 7.80 (d, J=8.34 Hz, 2H) 8.15 (br. s., 2H) 8.41-8.86 (m, 4H) 8.94 (s, 1H). MS m/z [M+H]+ 387.2.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C(N(CC)CC)C.[OH:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>C(O)C>[F:9][C:2]([F:1])([F:8])[C:3]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([OH:17])[CH2:19]1)=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: OC1CCCNC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(N1CCCC(O)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Ethyl trifluoroacetate (1.31 mL, 11.0 mmol) and triethylamine (1.68 mL, 12.0 mmol) were added to 3-hydroxypiperidine (1.01 g, 10.0 mmol) in ethanol (10 mL). The mixture was stirred at room temperature for 8 hours. Subsequently, the reaction mixture was concentrated and water was added. The mixture was then extracted with ethyl acetate and the extract washed with brine and dried over magnesium sulfate. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->2:1) gave 1.68 g (85%) of the desired compound as a colorless oil.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.[F:26][C:27]([F:35])([F:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][NH:19][C:18]1[CH:21]=[CH:22][C:15]([N:31]2[CH2:32][CH2:33][CH:28]([C:27]([F:35])([F:34])[F:26])[CH2:29][CH2:30]2)=[CH:16][C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CNc1ccc(N2CCC(C(F)(F)F)CC2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under argon sodium tert-butoxide (366 mg, 3.8 mmol) followed by palladium(II) acetate (22 mg, 0.1 mmol) and tri-tert-butylphosphine 10% in toluene (450 μL, 0.2 mmol) were added to a mixture of 4-bromo-2-nitro-N-methyl-aniline (440 mg, 1.9 mmol) and 4-(trifluoromethyl)piperidine (660 mg, 2.9 mmol) in toluene (7 mL). The reaction mixture was stirred at 100° C. overnight then allowed to cool and was concentrated. The crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C[Si]([C:14]#[CH:15])(C)C>C1COCC1.[Cu]I.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1)#[CH:15]
Reactant: CSc1nccc(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#Cc1ccnc(SC)n1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
To a solution of Pd(PPh3).CH2Cl2 (22 mg, 0.031 mmol) and PPh3 (17 mg, 0.065 mmol) in THF (200 mL), TEA (300 mL), and 4-Chloro-2-methylsulfanyl-pyrimidine (1.0 g, 6.75 mmol, 1 eq.) were added under argon. CuI (13 mg, 0.065 mmol) and trimethylsilylacetylene (725 mg, 7.25 mmol, 1.1 eq) were then added sequentially. The reaction mixture was heated at reflux for 8 h and cooled to rt. The precipitate was filtered off and washed with AcOEt. The filtrate solution was concentrated and the residue was diluted with DCM and 3 g of silica gel. The solvent was removed and the residue was loaded on silica column. The product was eluted with 10% AcOEt/hexanes to provide the desilylated product (540 mg, 3.6 mmol, 53%).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([O:13][CH3:14])[C:10]3[O:15][C:16]4[C:21]([C@@:22]5([CH2:27][CH2:26][O:25][C:24]([NH2:28])=[N:23]5)[C:9]=3[CH:8]=2)=[CH:20][C:19]([NH2:29])=[CH:18][CH:17]=4)[CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:28][C:24]1[O:25][CH2:26][CH2:27][C@:22]2([C:9]3[CH:8]=[C:7]([C:4]4[CH2:3][CH2:2][O:1][CH2:6][CH:5]=4)[N:12]=[C:11]([O:13][CH3:14])[C:10]=3[O:15][C:16]3[C:21]2=[CH:20][C:19]([NH:29][C:37](=[O:38])[C:34]2[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][N:35]=2)=[CH:18][CH:17]=3)[N:23]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: COc1nc(C2=CCOCC2)cc2c1Oc1ccc(N)cc1[C@@]21CCOC(N)=N1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(C2=CCOCC2)cc2c1Oc1ccc(NC(=O)c3ccc(Cl)cn3)cc1[C@@]21CCOC(N)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
To a solution of (S)-3-(3,6-dihydro-2H-pyran-4-yl)-1-methoxy-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.080 g, 0.203 mmol) in THF/MeOH (20.3 mL) were added 5-chloro-2-pyridinecarboxylic acid (0.035 g, 0.223 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.066 g, 0.223 mmol). The resulting reaction mixture was stirred at RT for 2 h. The mixture was quenched with sat. NaHCO3 and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated, chromatographed on silica gel using 0-5% MeOH/DCM and repurified by HPLC to afford a white solid as (S)—N-(2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-1-methoxy-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide (0.0401 g, 0.075 mmol, 37.0% yield).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([CH2:9][CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])#[N:8]>ClCCl>[C:7]([CH2:9][CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([Cl:4])=[O:14])#[N:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(CCCC#N)C(=O)O
Solvent: ClCCl
Product: CC(C)(CCCC#N)C(=O)Cl
Reaction time: 3 h

Procedure:
Oxalyl chloride (0.39 mL, 4.5 mmol) was added to a 0-5° C. solution of 5-cyano-2,2-dimethyl-pentanoic acid (0.462 g, 2.98 mmol) in 3 mL of dichloromethane, and the mixture was stirred for 3 h then concentrated to afford crude 5-cyano-2,2-dimethyl-pentanoyl chloride as a yellow oil, which was immediately used in the next step.
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]=1>[Pt]>[CH:5]1([Si:2]([Cl:4])([Cl:3])[Cl:1])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C1=CCCC1
Reactant: Cl[SiH](Cl)Cl
Agent: [Pt]
Product: Cl[Si](Cl)(Cl)C1CCCC1
Yield: 19 %

Procedure:
The reaction was performed by agitating the reaction mixture, which was prepared from 19.1 g (0.141 mole) of trichlorosilane, 9.2 g (0.135 mole) of cyclopentene and 0.13 g of the catalyst I corresponding to 23 ppm by weight as platinum based on the total amount of trichlorosilane and cyclopentene, in a glass flask at 30° C. for 22 hours under normal pressure. Only about 22% of the starting reactants had been reacted after the end of this reaction time as determined by the gas chromatographic analysis. Treatment of the reaction mixture after the reaction was performed in the same manner as in Example 1 to give 5.2 g (0.0256 mole) of cyclopentyl trichlorosilane in a yield of 19% as isolated based on the theoretical value.
Reaction SMILES: [SH2:1].[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[C:5]([CH3:11])[N:4]=1.C(N(CC)CC)C.CN(C)C=O>N1C=CC=CC=1>[NH2:2][C:3]1[C:8]([C:9](=[S:1])[NH2:10])=[CH:7][N:6]=[C:5]([CH3:11])[N:4]=1
Reactant: S
Reactant: Cc1ncc(C#N)c(N)n1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ncc(C(N)=S)c(N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrogen sulfide is passed through a mixture of 4-amino-2-methyl-5-pyrimidinecarbonitrile (6.707 g., 0.050 m.), triethylamine (7.0 ml., 0.050 m.), dimethylformamide (25 ml.) and pyridine (100 ml.) with stirring for 3 hours at ambient temperature. The mixture is poured into ice water (500 ml.) and the cream-colored solid which separates is collected by filtration, washed with water, dried at 110° C./0.1 mm. The yield of product melting at 260° C. dec. (uncorr.) is 7.663 g. (91.1%). This material is recrystallized from dimethylformamide-water (Darco G-60) affording colorless crystals melting at 264° C. dec. (uncorr.) in a yield of 5.110 g. (60.8%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[Br:16][C:17]1[C:18](=O)[NH:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(=O)(O)[O-].[Na+]>O>[Br:16][C:17]1[C:18]([Cl:3])=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(C(F)(F)F)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: FC(F)(F)c1cnc(Cl)c(Br)c1
Temperature: 120 °C
Yield: 77.2 %

Procedure:
To phosphorous oxychloride (2.02 mL, 21.6 mmol) was added quinoline (1.34 mL, 11.2 mmol) followed by 3-bromo-5-trifluoromethyl-2(1H)-pyridone (5.0 g, 20.07 mmol). The mixture was heated at 120° C. for 3 hrs, then cooled to 100° C., whn water (10 mL) was carefully added. After cooling to room temperature, saturated sodium bicarbonate was added (100 mL) and the mixture extracted with ethyl acetate (2×100 mL). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the product as a liquid (4.05 g, 15.5 mmol, 75% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])CCC.CON(C)[C:26](=[O:42])[CH:27]([O:40][CH3:41])[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]([CH3:39])=[N:37][N:38]=2)=[CH:30][CH:29]=1>C1COCC1>[CH3:41][O:40][CH:27]([C:28]1[CH:29]=[CH:30][C:31]([C:34]2[O:35][C:36]([CH3:39])=[N:37][N:38]=2)=[CH:32][CH:33]=1)[C:26]([C:15]1[O:14][C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17][CH:16]=1)=[O:42]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a solution of 2-(3,4,5-trimethoxyphenyl)furan (1.4 g, 5.98 mmol) in anhydr THF (70 mL) under argon in an oven-dried flask cooled to −78° C. was added n-butyl lithium (2.5 M in hexanes; 2.63 mL, 6.28 mmol) dropwise. After stirring for 1 hr at −78° C., a solution of N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide (1.75 g, 6.0 mmol) in THF (5 mL) was added dropwise. After stirring for 25 min, the mixture was allowed to warm to room temp while stirring for 2 hrs. The reaction was quenched with the addition of saturated aqueous NH4Cl then brine and EtOAc were added. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (60% EtOAc-hexanes) gave 2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)ethanone as a fluffy yellow solid (0.81 g, 29% yield). MS: m/z 465.3 [M+H]+.