Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:13][C:14]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].S(=O)(=O)(O)O.B(O)(O)O>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:15]=1[C:16]([O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=1)=[O:17]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: CCCCCc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(OC(=O)c2ccc(O)cc2Cl)cc1

Procedure:
To a suspension of p-pentylphenol (0.15 mole) and 2-chloro-4-hydroxybenzoic acid (0.10 mole) in toluene (500 ml.) is added concentrated sulfuric acid (0.5 g.) and boric acid (0.31 g.) (5 mole percent). The reaction mixture is refluxed for 29 hours under a Dean-Stark trap. The solvent is then removed under reduced pressure and the product is washed with ligroin. The resulting 4-pentylphenyl 2-chloro-4-hydroxybenzoate is recrystallized from an ethanol/water mixture to give 25.6 g., 81% of pure product, m.p. 149°-151°C.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)(O)=[O:2].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)=[O:2])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: NCc1ccc(F)cc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1ccc(F)cc1
Yield: 51 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.20 g) obtained in Example 9 and 4-fluorobenzylamine to give Compound 29 (0.13 g, 51%) as a white solid.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH3:55][C:56]([O:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)([CH3:58])[CH3:57]>CN(C)C(=O)C>[CH3:58][C:56]([O:59][CH:60]1[CH2:61][CH2:62][N:63]([C:4]([C:3]2[CH:7]=[C:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)[CH:9]=[CH:10][CH:2]=2)=[O:6])[CH2:64][CH2:65]1)([CH3:55])[CH3:57]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CC(C)(C)OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)CC1
Reaction time: 0.08 h

Procedure:
To 20 ml vial was added 3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid (1b) (50 mg, 0.178 mmol). To this was added N,N-dimethylacetamide (2 mL) and triethylamine (70 μL, 0.445 mmol). This mixture was allowed to stir for 5 mins before addition of O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate, this solution was also allowed to stir for a further 5 minutes. A solution of 4-[(2-methylpropan-2-yl)oxy]piperidine hydrochloride (35 mg, 0.178 mmol) in N,N-dimethylacetamide (1 mL) and triethylamine (25 μl, 0.179 mmol) was then added and the reaction left to stir at ambient temperature for 2 hours before being purified by preparative HPLC to afford the desired compound; m/z (LC-MS, ESI+), RT=1.74 (M+H 420.4).
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C:13](=[O:35])[C@@H:14]2[C@:31]3([CH3:32])[C@H:17]([C@H:18]4[C:28](=[CH:29][CH2:30]3)[C@:26]3([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[CH:24]=[CH:25]3)[CH2:20][CH2:19]4)[CH2:16][C@H:15]2[CH3:34])(=O)=O)=CC=1.[C:36]12([NH:46][C:47]3[N:52]=[C:51]([N:53]4[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)[CH:50]=[C:49]([N:59]4[CH2:63][CH2:62][CH2:61][CH2:60]4)[N:48]=3)[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2>>[C:36]12([NH:46][C:47]3[N:52]=[C:51]([N:53]4[CH2:54][CH2:55][N:56]([CH2:12][C:13](=[O:35])[C@@H:14]5[C@:31]6([CH3:32])[C@H:17]([C@H:18]7[C:28](=[CH:29][CH2:30]6)[C@:26]6([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[CH:24]=[CH:25]6)[CH2:20][CH2:19]7)[CH2:16][C@H:15]5[CH3:34])[CH2:57][CH2:58]4)[CH:50]=[C:49]([N:59]4[CH2:63][CH2:62][CH2:61][CH2:60]4)[N:48]=3)[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc(Br)cc1
Reactant: c1c(N2CCCC2)nc(NC23CC4CC(CC(C4)C2)C3)nc1N1CCNCC1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCCC3)nc(NC34CC5CC(CC(C5)C3)C4)n2)CC1
Yield: 79.94 %

Procedure:
The reaction of 21-(4-bromobenzenesulfonyloxy)-16α-methylpregna-1,4,9(11)-triene-3,20-dione with 2-(1-adamantylamino)-4-(1-piperazinyl)-6-pyrrolidinopyrimidine as described in Example 6 gives the title compound in a yield of 79.94%, m.p.:155°-172° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:26][NH:27][CH3:28]>O>[CH3:26][N:27]([CH2:20][C:11]1[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)[CH:10]=1)[CH3:28]
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Reactant: CNC
Solvent: O
Product: Cc1ccc(-c2cc(CN(C)C)c(=O)n(CC(C)C)n2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To 6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one (100 mg, 0.27 mmol) was added a 40% aqueous dimethylamine (1 mL), and the mixture was stirred at 80° C. for 2 hours. The temperature of the reaction mixture was allowed to drop back to room temperature, and then, water was added. The mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel [chloroform/methanol (40/1)] to yield the title compound as a yellow oil (69.7 mg, 80.9%).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]4=[O:37])=[CH:23][C:22]=3[F:38])=[C:17]([F:39])[CH:16]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>ClCCl>[F:38][C:22]1[CH:23]=[C:24]([N:27]2[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]2=[O:37])[CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH2:11][CH:10]([CH2:9][OH:8])[O:14][N:13]=2)=[CH:16][C:17]=1[F:39]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO[Si](C)(C)C(C)(C)C)C4)cc3F)c(F)c2)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO)C4)cc3F)c(F)c2)C(=O)O1
Reaction time: 5 h
Yield: 37.9 %

Procedure:
N-[((5S)-3-{4′-[5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydroisoxazol-3-yl]-2,2′-difluoro-1,1′-biphenyl-4-yl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (416 mg, 0.74 mmol) was dissolved in dichloromethane (25 ml) at room temperature. A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.82 ml, 0.82 mmol) was added and the reaction mixture stirred for 300 minutes. Water (50 ml) was added and the dichloromethane layer separated, dried over magnesium sulfate, filtered then concentrated in vacuo onto silica (2 ml). This was purified by chromatography (20 g silica gel bond elut; 0 to 6% methanol/dichloromethane) to yield 125 mg (38%) of the desired compound.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1([OH:10])[CH2:9][O:8][CH2:7]1)([CH3:5])[CH3:4].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18](=O)[O:19]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:18](=[O:19])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[O:10][C:6]1([CH:3]([CH3:5])[CH3:4])[CH2:9][O:8][CH2:7]1
Reactant: CC(C)C1(O)COC1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C1(OC(=O)Oc2ccccn2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (331 mg, 8.26 mmol) in THF (25 mL) was added 3-isopropyloxetan-3-ol (800 mg, 6.89 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (1489 mg, 6.89 mmol) in THF (25 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage eluting with 20% EtOAc in hexanes to afford the desired product 3-isopropyloxetan-3-yl pyridin-2-yl carbonate (320 mg, 20.2% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) d 8.47-8.39 (m, 1H), 7.86-7.78 (m, 1H), 7.31-7.24 (m, 1H), 7.15 (d, J=8.0 Hz, 1H), 4.89 (d, J=8.5 Hz, 2H), 4.67 (d, J=8.5 Hz, 2H), 2.53 (dt, J=13.7, 7.0 Hz, 1H), 1.13 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[CH2:13]([C@@H:15]1[O:17][CH2:16]1)Cl>>[O:17]1[CH2:16][C@H:15]1[CH2:13][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[O:12]1[CH2:7][CH2:8]1
Reactant: ClC[C@H]1CO1
Reactant: O=C1CCCc2c(O)cccc21
Product: C1CO1
Product: O=C1CCCc2c(OC[C@@H]3CO3)cccc21

Procedure:
reacting 5-hydroxy-3,4-dihydro-1(2H)-naphthalenone with (R)-(-)-epichlorhydrine, in an aprotic solvent in the presence of a strong base at a temperature of over 90° C., to give the intermediate chiral oxirane (S)-5-(2,3-epoxypropoxy)-3,4-dihydro-1(2H)-naphthalenone with an optical purity greater than 95%, and then,
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[C:16]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:15](=[O:25])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:26][C:27]([F:32])([F:31])[C:28]([O-:30])=[O:29].[CH:33]1([N:38]2[CH2:43][CH2:42][NH2+:41][CH2:40][C:39]2=[O:44])[CH2:37][CH2:36][CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C.C(Cl)Cl>[F:26][C:27]([F:32])([F:31])[C:28]([O-:30])=[O:29].[CH:33]1([N:38]2[CH2:43][CH2:42][N:41]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[CH:17]=[C:16]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:15](=[O:25])[NH:14][NH+:13]=3)=[O:6])[CH2:40][C:39]2=[O:44])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C1C[NH2+]CCN1C1CCCC1
Reactant: O=C(O)c1cc(Cc2cc(C(F)(F)C(F)(F)F)c(=O)[nH]n2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2cc(C(F)(F)C(F)(F)F)c(=O)[nH][nH+]2)ccc1F)N1CCN(C2CCCC2)C(=O)C1

Procedure:
OO7, 4-cyclopentyl-3-oxopiperazin-1-ium trifluoroacetate (1 eq.), TBTU (1 eq.) and N-methyl-morpholine (2.2 eq.) were stirred for 2 h in DMF. The product was purified by preparative HPLC (water/MeCN, 0.1% TFA as eluents) and desired pooled product fractions were lyophilized to afford a white powder. The powder was dissolved in DCM and washed with sat. aq. NaHCO3. The organic phase was dried (Na2SO4), filtered and concentrated to dryness to afford the product as colourless oil. 1H-NMR (300 MHz, DMSO-d6) δ: 13.52 (1H, s), 7.90 (1H, s), 7.46-7.22 (3H, m), 4.82-4.65 (1H, m), 4.15 (1H, s), 4.03 (2H, s), 3.80 (2H, s), 3.42-3.20 (3H, m), 1.80-1.40 (8H, m). MS (ES) C23H22F6N4O3 requires: 516, found: 517 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:45][NH2:46]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:45][NH:46]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)NC2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NC2CCCCC2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide (235 mg, 0.538 mmol), 5 ml of EtOH, Hunig's base (0.376 ml, 2.153 mmol), and hydrazine anhydrous (0.101 mL, 3.23 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached 100° C. while heating, the solid in the mixture was all dissolved. After overnight, there were yellow suspension as well as some black colored solid formed. LCMS showed mainly product. The black solid and the yellow solid were carefully separated due to the black solid being heavier than yellow solid in the CH3OH solvent. The yellow solid in CH3OH was filtered and washed with CH3OH to remove the color and afford the title compound (157 mg) as a white solid. LC-MS (ES) m/z=449 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.05-1.35 (m, 8H), 1.50-1.88 (m, 9H), 2.24 (s, 1H), 2.90 (s, 1H), 3.46-3.60 (m, 1H), 5.38 (s, 2H), 6.07 (s, 2H), 6.57 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:51][C:50]=2[CH:59]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:47]=[CH:48][C:49]5[O:53][C:52]([CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:51][C:50]=5[CH:59]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCOCc1cc2cc(OB([O-])[O-])ccc2o1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCOCc1cc2cc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.41 g) was added toluene/ethanol/water (10/1/1,19.2 ml) and then were added 2-(propoxymethyl)-1-benzofuran-5-yl borate (0.22 g) and potassium carbonate (0.24 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (45 mg), and the mixture was refluxed for 14 hours, cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=4/1) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[2-(propoxymethyl)-1-benzofuran-5-yl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 136) (184 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]2[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]2=[O:23])=[C:11]([CH3:24])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH3:24])[C:12]([CH:16]2[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]2=[O:23])=[C:13]([CH3:15])[CH:14]=1
Reactant: [H][H]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)CCCC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(O)cc(C)c1C1C(=O)CCCC1=O

Procedure:
To a solution of 2-(4-benzyloxy-2,6-dimethylphenyl)cyclohexane-1,3-dione (0.57 g, 0.0018 mol) in ethyl acetate (30 ml) and methanol (530 ml) is added 5% palladium on carbon (0.100 g), and the suspension is then stirred under 4 bar hydrogen pressure for 5 hours. The suspension is filtered through diatomaceous earth and the filtrate evaporated under reduced pressure to afford 2-(4-hydroxy-2,6-dimethylphenyl)cyclohexane-1,3-dione as a grey solid.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:38])[O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][Si](C(C)(C)C)(C)C)=[CH:18][C:17]=3[O:30][Si](C(C)(C)C)(C)C)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-]>CO>[CH:1]1([NH:7][C:8](=[O:38])[O:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[OH:30])[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](OC(=O)NC3CCCCC3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [F-]
Solvent: CO
Product: O=C(NC1CCCCC1)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl cyclohexylcarbamate (28 mg), methanol (10 ml) and Amberlyst fluoride resin (0.3 g) were stirred at room temperature for 72 hr. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:3 v/v) to give the title compound as a white solid (6 mg, 36%); δH (CD3OD) 1.10-2.12 (18H, m), 2.70-2.82 (1H, m), 4.46-4.60 (1H, m), 6.18-6.30 (2H, m), 6.80-6.92 (1H, m); m/z (ES+) 334 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:25]=[CH:24][C:17](CN(O)C(N)=O)=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[OH-:26].[Na+].Cl[C:29]([O:31]CC)=[O:30]>O>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([N:8]3[C:29](=[O:30])[O:31][N:4]([CH3:5])[C:3]3=[O:26])=[CH:24][CH:25]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: [OH-]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(CN(O)C(N)=O)cc1
Agent: [Na+]
Solvent: O
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(-n2c(=O)on(C)c2=O)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirred solution of N-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzyl]-N-hydroxyurea (346 mg, 1.0 mmol) (obtained from preparation 19) in water (2 ml) was added 1N NaOH (3 ml) followed by ethyl chloroformate (191 μl, 217 mg, 2.0 mmol) and stirred for 1 h at 30° C. The reaction mixture was diluted with water, acidified to pH 3.0 and extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the title compound (283 mg, 76%).
Reaction SMILES: C([Li])CCC.Cl[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]#[C:8][CH:9]1[CH2:11][CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: C#CCCCCl
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CC1CC1)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.1 %

Procedure:
To a solution of n-butyllithium (2.5M in hexanes, 159 mL, 0.398 mol) in THF (800 mL) at −10° C. under nitrogen, add 5-chloropentyne (20 g, 0.195 mol) dropwise, keeping the temperature below 10° C. After the addition is complete, allow the reaction to warm to room temperature and stir for 6 hours, then add tributyltin chloride (70 g, 0.215 mol) and stir overnight. Pour the reaction mixture into hexanes (500 mL), wash with saturated sodium bicarbonate (300 mL) and brine (300 mL), dry with sodium sulfate, filter, and concentrate to afford the title compound (70 g, 100%) which can be used without further purification: mass spectrum (m/e): 357 (M+H+); 1H NMR (CDCl3) δ 1.70-1.49 (m, 6H), 1.49-1.24 (m, 7H), 1.10-0.65 (m, 19H).
Reaction SMILES: [C:1]([C:3]1[C:8](Br)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:1]([C:3]1[C:8]([C:13]2[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2cccnc2C#N)cc1
Yield: 34 %

Procedure:
Under nitrogen, 13.91 g (76 mmol) of 2-cyano-3-bromopyridine from step 2 and 11.41 g (84 mmol) of 4-tolylboronic acid from step 3 were treated with 2.65 g (2.3 mmol) of tetrakis(triphenylphosphine)palladium zero, 155 mL of toluene, 60 mL of ethanol, and 77 mL of 2M aqueous sodium carbonate. The reaction mixture was heated to reflux and vigorously stirred overnight. The product crystallized from the reaction mixture after several days at ambient temperature. Filtration provided 5.02 g (34%) of 2-cyano-3-(4-tolyl)pyridine as a colorless solid: mp 136°-138° C.; NMR (CDCl3) δ2.44 (s, 3H), 7.34 (d, J=8 Hz, 2H), 7.47 (d, J=8 Hz, 2H), 7.56 (dd, J=8 and 5 Hz, 1H), 7.85 (dd, J=8 and 2Hz, 1H), 8.68 (dd, J=5 and 2 Hz, 1H); MS (70 eV) m/e (rel intensity) 194 (100).
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][C:3]=1[CH:18]=O.C(N(CC)CC)C.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:28][SH:29].[OH-].[K+]>N1C=CC=CC=1.O>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:5]2[CH2:6][CH2:7][C:2]3[S:29][C:28]([C:27]([O:31][CH2:32][CH3:33])=[O:30])=[CH:18][C:3]=3[CH2:4]2)(=[O:9])=[O:10])=[CH:16][CH:15]=1
Reactant: CCOC(=O)CS
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Cl)=C(C=O)C2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(s1)CCN(S(=O)(=O)c1ccc(C)cc1)C2
Reaction time: 8 h

Procedure:
To a solution of a 4-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,5,6-tetrahydropyridine-3-carbaldehyde (1 eq) obtained from step II in pyridine was added triethyl amine (1.5 eq.), ethyl thioglycolate (1 eq.) at 0° C. and the reaction mixture was stirred for overnight. A solution of KOH (1.5 eq) in water was added at 0° C. and the reaction was continued at room temperature for 1 h Reaction was quenched with water and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded ethyl 5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate.