Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1[C:36]1[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[C:39]([F:45])=[CH:38][C:37]=1[O:46][CH3:47])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:10][N:9]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(OCC)(=O)C>[F:55][C:2]([F:1])([F:56])[C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([C:51]([F:52])([F:54])[F:53])[CH:50]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:27]=1[C:36]1[CH:41]=[C:40]([CH:42]([CH3:43])[CH3:44])[C:39]([F:45])=[CH:38][C:37]=1[O:46][CH3:47])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1
Reactant: COc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)c(-c2cc(C(C)C)c(F)cc2OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)O)cn2)c(-c2cc(C(C)C)c(F)cc2OC)cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 83.4 %

Procedure:
To tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4′-fluoro-5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (129 mg) is added a 4N-hydrogen chloride/dioxane solution (3 ml) and the mixture is stirred at room temperature for 7 hours. To the reaction solution are added a saturated aqueous sodium hydroxide solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4′-fluoro-5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid (100 mg). MS (m/z): 740 [M+H]+
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][C:64]([P:67](=[O:74])([O:71][CH2:72][CH3:73])[O:68][CH2:69][CH3:70])([F:66])[F:65]>>[CH2:69]([O:68][P:67]([C:64]([F:66])([F:65])[CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][NH:55][C:20](=[O:21])[C@@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:74])[O:71][CH2:72][CH3:73])[CH3:70]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC

Procedure:
The title compound was prepared from (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-((R)-2-dodecanamido-3-(dodecyloxy)propylthio)propanoic acid (1.0 eq, from example 26, step 8) and diethyl 3-(2-(2-aminoethoxy)ethoxy)-1,1-difluoropropylphosphonate (1.2 eq, from example 22, step 3) by following the procedure described for example 26, step 9.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[C:17]([NH2:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][C:21]([CH3:23])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:5]1[C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[S:8][C:7]=2[C:17](=[O:18])[NH:19][C:21]1([CH3:23])[CH3:20])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=O
Reactant: CCCCNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Temperature: 70 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
A mixture of 3-(butylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), acetone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 days at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 12 g silica gel, hexane to ethyl acetate) to afford the title compound (0.0879 g, 70%) as a yellow solid:
Reaction SMILES: COC1C=CC=CC=1S[CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36][C:37]([F:47])([F:46])[O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[SH:45].C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:26][C:22]([S:21][C:18]1[S:17][C:16]([NH:15][C:14]([N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[CH2:12][CH2:11][CH2:10][S:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[O:38][C:37]([F:36])([F:46])[F:47])=[O:28])=[N:20][CH:19]=1)([CH3:27])[C:23]([OH:25])=[O:24]
Reactant: FC(F)(F)Oc1ccccc1S
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccccc2OC(F)(F)F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 2-trifluoromethoxy -thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)cc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)cc1Br
Reaction time: 3 h

Procedure:
2-Bromo-4-fluorobenzoic acid (1.533 g, 7 mmol, commercially available from e.g. Sigma-Aldrich, Apollo or Fluorochem) in dichloromethane (DCM) (40 mL) was cooled to 0° C., before oxalyl chloride (0.674 mL, 7.70 mmol) and a few drops of DMF (cat.) were added. The solution was then stirred under argon for 3 hours. The solvent was then evaporated in vacuo and the remaining residue was azeotroped with toluene (2×20 mL) to yield the product in 1.645 g.
Reaction SMILES: [Si](O[C@H](CO[Si](C(C)(C)C)(C)C)C[N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20]Br)=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:22]#[N:23])(C(C)(C)C)(C)C.[NH:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]2[C:41]3[CH:48]=[C:47]([CH2:49][C:50]([F:53])([F:52])[F:51])[S:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:52][C:50]([F:51])([F:53])[CH2:49][C:47]1[S:46][C:42]2[N:43]=[CH:44][N:45]=[C:40]([NH:39][CH:36]3[CH2:35][CH2:34][N:33]([CH2:20][C:16]4[CH:15]=[C:14]5[C:19](=[CH:18][CH:17]=4)[NH:11][C:12]([C:22]#[N:23])=[CH:13]5)[CH2:38][CH2:37]3)[C:41]=2[CH:48]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Cn1c(C#N)cc2cc(CBr)ccc21)O[Si](C)(C)C(C)(C)C
Reactant: FC(F)(F)Cc1cc2c(NC3CCNCC3)ncnc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc2cc(CN3CCC(Nc4ncnc5sc(CC(F)(F)F)cc45)CC3)ccc2[nH]1
Yield: 33.8 %

Procedure:
58 mg of (S)-1-(2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-5-(bromomethyl)-1H-indole-2-carbonitrile (0.1 mmol) and 31 mg of N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (0.12 mmol) were dissolved in 0.2 mL of DCM. 26 mg of DIPEA (0.2 mmol) was added to that solution and reaction mixture was stirred for 18 hs. Then reaction mixture was directly loaded on silica gel column and the product was eluted with DCM-MeOH 30:1. After evaporation of solvent TBDMS-protected intermediate was dissolved in 0.2 mL of MeOH and 0.02 mL of 12M HCl was added. The homogenous reaction mixture was stirred overnight and then all volatiles were removed in vacuo. The residue was quenched ammonia and extracted with ethyl acetate. Combined organic fractions were dried over MgSO4 and concentrated. The residue was purified on silica gel column using DCM-MeOH 20:1 to afford 15.9 mg of 5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (Compound 188). Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. Monohydrochloride salt exists as a mixture of rotomers in approximate ratio 10:1, NMR is described for the major one: 1H NMR (600 MHz, MeOD-d4): 8.63 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.77 (d, 1H, J=8.6 Hz), 7.63 (d, 1H, J=8.6 Hz), 7.37 (s, 1H), 4.57 (m, 1H), 4.56 (m, 1H), 4.50 (s, 2H) 4.37 (m, 1H), 4.04 (m, 1H), 3.99 (q, 2H, J=10.3 Hz), 3.65 (m, 2H), 3.60 (d, 2H, J=5.5 Hz), 3.29 (m, 2H), 2.37 (m, 2H), 2.12 (m, 2H). 13C NMR (150 MHz, MeOD-d4): δC 157.45, 150.99, 139.90, 132.27, 129.16127.89, 127.37, 127.00, 125.54, 123.11, 122.50, 118.58, 114.32, 114.25, 113.35, 113.31, 72.35, 64.85, 61.99, 52.44, 49.82, 48.12, 35.32 (q, J=33 Hz), 29.64. ESI MS [MH+]: 545.1941.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C.O>[N:20]([CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)N1CC(c2ccccc2)c2ccccc21
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NCC(=O)N1CC(c2ccccc2)c2ccccc21
Yield: 68.3 %

Procedure:
A solution of 4.0 g of N-chloroacetyl-3-phenylindoline and 1.1 g of sodium azide in 70 ml of 80% aqueous ethanol was refluxed for one hour. After cooling, the solution was diluted with 100 ml of water and extracted with methylene chloride. Evaporation of the solvent gave 2.8 g of the desired N-azidoacetyl-3-phenylindoline having a melting point of 72°-3° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:22](=[O:23])[O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2ccncc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccncc2)cc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 4-(4-pyridinyl)aniline (50 mg) in dichloromethane (1.50 mL) and pyridine (356.4 μL) was added dropwise benzyloxycarbonyl chloride (75.5 μL) at ambient temperature and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was concentrated in vacuo and water (10 mL) was added to the residue. The aqueous solution was extracted with ethyl acetate (15 mL) and the organic layer was washed successively with saturated sodium bicarbonate aqueous solution and brine, then dried and concentrated. The residual solid was triturated with diisopropylether (2.0 mL) to give benzyl [4-(4-pyridinyl)phenyl]carbamate (70.3 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1cccs1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) and thiophene-2-sulfonyl chloride (80 mg, 0.437 mmol), the title compound was obtained as a white solid (93 mg, 65% yield). MS (ESI): 489.9 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=O.[CH:11](=O)C1C=CC=CC=1>[Pd]>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:8])[CH3:11]
Reactant: OCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Pd]
Agent: O=O
Product: CC(=O)c1ccccc1

Procedure:
Expectedly, benzylic alcohols such as PhCH2OH, 4-CH3OPhCH2OH, 4-CF3PhCH2OH, and PhCHOHCH3 were also reactive (0.1 mmol substrate, 5 μmol Pd-POM-1, 1 ml TFT, 2 bar O2, and 110° C. for 20 minutes), all yielding the corresponding benzaldehyde derivatives or acetophenone with >95% yields with no observed by-products.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: NCC(O)c1cccc(Br)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Br)c2)cc1
Yield: 56.8 %

Procedure:
Following a procedure similar to that described in Example 3, but using 3.0 g of 2-amino-1-(3-bromophenyl)ethanol (prepared as described in Preparation 41), 3.67 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 3.1 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.33 g of the title compound were obtained having an Rf=0.25 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[N:6]=[C:7]([NH:10][C:11]2[CH:18]=[C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:14]([CH:15]=O)=[CH:13][N:12]=2)[S:8][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:1][N:2]([CH2:15][C:14]1[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[CH:18][C:11]([NH:10][C:7]2[S:8][CH:9]=[C:5]([CH3:4])[N:6]=2)=[N:12][CH:13]=1)[CH3:3]
Reactant: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(C=O)cn2)n1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(CN(C)C)cn2)n1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
Dimethylamine (0.374 mL, 0.747 mmol) was added to a solution of 6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)nicotinaldehyde (0.090 g, 0.249 mmol) in THF (3 mL) and stirred for 10 minutes. Sodium triacetoxyborohydride (0.264 g, 1.25 mmol) was added and the reaction mixture was stirred for an additional 30 minutes. The mixture was quenched with saturated sodium bicarbonate, partitioned between ethyl acetate and water, washed with brine, dried, and concentrated. The residue was dissolved in THF (2 mL), 1M HCl in ether was added, the solution was diluted in hexanes (5 mL), triturated for 15 minutes, filtered, dried to afford 5-((dimethylamino)methyl)-N-(4-methylthiazol-2-yl)-4-(naphthalen-1-yloxy)pyridin-2-amine (0.071 g, 73.0% yield) as a white solid. 1H NMR (DMSO d6) δ 10.88 (bs, 1H), 8.58 (s, 1H), 8.09 (d, 1H), 7.98 (d, 1H), 7.90 (d, 1H), 7.52-7.67 (m, 4H), 6.67 (s, 1H), 6.37 (s, 1H), 4.54 (s, 2H), 2.88 (s, 6H), 2.18 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]([CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:29]([C:31]1[C:32](=[C:42]([C:45]#[N:46])[C:43]#[N:44])[O:33][C:34]([CH3:41])([C:37]([F:40])([F:39])[F:38])[C:35]=1[CH3:36])#[N:30]>C(O)C>[CH2:25]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:20][C:19]([CH:21]=[CH:36][C:35]3[C:34]([CH3:41])([C:37]([F:40])([F:38])[F:39])[O:33][C:32](=[C:42]([C:43]#[N:44])[C:45]#[N:46])[C:31]=3[C:29]#[N:30])=[CH:18][CH:17]=2)=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(CCCC)c1ccc(C=CC=Cc2ccc(C=O)s2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)c(OC)c1
Temperature: 50 °C
Yield: 76 %

Procedure:
In 8 ml of ethanol were dissolved 230 mg (0.58 mmol) of 5-[4-(4-dibutylamino-2-methoxyphenyl)-1,3-butadienyl]thiophene-2-carboaldehyde and 160 mg (0.63 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene) propanedinitrile. After the mixture was stirred with heating at 50° C. for 2 hours, the product was separated by filtration and washed with ethanol. The product was purified by silica gel column chromatography to give 279 mg of a black crystal (yield: 76.2%; mp: 161-162° C.)
Reaction SMILES: [CH2:1]([C:16]([OH:18])=[O:17])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].O[CH2:20][CH:21]=[C:22]([CH2:24][CH2:25][CH:26]=[C:27]([CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH3:28])[CH3:23].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C1(C)C=CC=CC=1>[CH2:1]([C:16]([O:18][CH2:20][CH:21]=[C:22]([CH2:24][CH2:25][CH:26]=[C:27]([CH2:29][CH2:30][CH:31]=[C:32]([CH3:33])[CH3:34])[CH3:28])[CH3:23])=[O:17])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH3:9])[CH3:4]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCC(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCOC(=O)CC=C(C)CCC=C(C)CCC=C(C)C
Yield: 78.7 %

Procedure:
A mixture of farnesyl carboxylic acid (5.0 g), farnesol (4.44 g) and triethylamine (4.85 g) was added dropwise at room temperature to a stirred solution of 2-chloro-1-methylpyridinium iodide (5.61 g) in 40 ml of toluene. After complete addition, the reaction mixture was heated on boiled water bath for three hours. After cooling, the mixture was washed with water and dried (Na2SO4). The solvent was removed in vacuo and gave a pale yellow oil. This material was purified by silica gel chromatography by using n-hexane and gave 7.15 g of the titled compound.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([OH:10])[C:8]#[CH:9]>C(NC(C)C)(C)C.[Cu]I>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:9]#[C:8][CH2:7][OH:10]
Reactant: C#CCO
Reactant: Ic1cccs1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: OCC#Cc1cccs1
Yield: 72.4 %

Procedure:
To a suspension of tetrakis (triphenylphosphine)palladium (300 mg, 0.25 mmol) and copper (I) iodide (100 mg, 0.50 mmol) in diisopropylamine (100 ml) under nitrogen was added 2-iodothiophene (6.3 g, 30 mmol). After stirring 1.5 h at room temperature a solution of propargyl alcohol (3.0 g, 33 mmol) in diisopropylamine (50 ml) was added. After 16 h at room temperature the mixture was filtered and concentrated in vacuo. The residue was submitted to flash chromatography using dichloromethane as eluent to give 3.0 g (73%) of 3-(2-thienyl)-2-propyn-1-ol as a crude product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:4]1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:34](O)=[O:35].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([N:5]2[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][C:34](=[O:35])[C:33]3[CH:32]=[C:31]([O:30][CH3:29])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=3)[CH2:4]2)=[O:28])=[CH:15][CH:16]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: NCC1CCN(C(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(C(=O)NCC2CCN(C(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-aminomethyl-pyrrolidin-1-yl)-6,6-bis-(4-fluoro-phenyl)-hexan-1-one (0.69 g, 1.78 mmol) in dry CH2Cl2 (40 ml) was added 3,4,5-trimethoxy benzoic acid (0.38 g, 1.78 mmol) under nitrogen. To the reaction was added EDC (0.68 g, 3.56 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give a desired product in good yield
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.CO.[NH4+:12]>>[NH2:12][CH2:3][C@@H:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[OH:1]
Reactant: [NH4+]
Reactant: c1cncc([C@@H]2CO2)c1
Solvent: CO
Product: NC[C@H](O)c1cccnc1

Procedure:
The title compound was prepared from 3-[(2R)-oxiranyl]pyridine (which was obtained in Example 134) and saturated ammonium methanol in substantially the same manner, as described in Example 124. The product was obtained as a brown oil; 1H NMR (300 MHz, DMSO-d6) δ 1.70 (brs, 2 H), 2.62–2.74 (m, 2 H), 4.46–4.50 (m, 1 H), 5.20 (brs, 1 H), 7.30–7.34 (m, 1 H), 7.68–7.71 (m, 1 H), 8.42–8.50 (m, 2 H); MS (ES) m/z: 139 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][C:4]=1[N+:11]([O-])=O.[Na+].[CH3:15][S:16]([O-:18])=[O:17].O>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:5][C:4]=1[NH2:11]
Reactant: COc1ccc(CCl)cc1[N+](=O)[O-]
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CS(C)(=O)=O)cc1N
Temperature: 80 °C
Yield: 51.6 %

Procedure:
To a solution of 4-methoxy-3-nitrobenzyl chloride (3.09 g, 15.3 mmol) in 75 mL of absolute ethanol was added methanesulphinic acid sodium salt (3.1 g, 30.7 mmol). The reaction was heated to 80° C. for 16 h. The reaction was cooled to room temperature and poured into water and the aqueous layer was extracted with ethyl acetate. Combined organics were dried over anhydrous MgSO4, filtered, concentrated onto silica gel and purified by flash chromatography with ethyl acetate/hexanes as the eluent. The fractions containing the desired product were concentrated to dryness, then redisolved in absolute ethanol and 10% palladium on carbon (500 mg) was added and the reaction was placed on the Fischer-Porter hydrogenation apparatus and treated with 50 psi of H2 gas overnight to give 2-(methyloxy)-5-[(methylsulfonyl)methyl]aniline (1.7 g, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 6.74 (d, J=8.2 Hz, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.52 (d, J=8.2, 2.2, 1H), 4.76 (s, 2H), 4.19 (s, 2H), 3.72 (s, 3H).