Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9](I)[O:8][C:7]=12.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1.O>[F:12][C:13]([F:27])([F:28])[C:14]1[CH:15]=[C:16]([C:9]2[O:8][C:7]3=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]3[CH:10]=2)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1nccc2cc(I)oc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1cc(-c2cc3ccnc(Cl)c3o2)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 73.7 %

Procedure:
In a three-neck flask was placed a mixture of 7-chloro-2-iodofuro[2,3-c]pyridine (1.00 g, 3.58 mmol), 3,5-bis(trifluoromethyl)phenyl boronic acid (0.92 g, 3.6 mmol), 1,4-dioxane/water (50 mL/10 mL) and K2CO3 (0.74 g, 5.38 mmol). After the suspension was degassed with nitrogen for 15 min, (PPh3)2PdCl2 (0.12 g, 0.17 mmol) was added and the mixture was degassed with nitrogen for 5 min. The resultant mixture was stirred at 50° C. for 48 h under nitrogen. The mixture was then cooled to RT and the solvent was evaporated to give a black residue, which was purified by flash chromatography (2% MeOH:DCM) to afford 965 mg (74%) of the title compound as a white crystalline. 1H NMR (300 MHz, CDCl3): δ 7.06 (s, 1H), 7.50 (m, 4H), 7.94 (dd, J=1.5 Hz, 2.4 Hz, 1H), 8.19 (d, J=5.1 Hz, 1H).
Reaction SMILES: C(N(CC)CC[N:6]1[C:14]2[CH:13]=[CH:12][C:11](NC(=O)CN(CCOCC3C=CC=CC=3)CC3C=CC=CC=3)=[C:10]3[O:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=4[C:8]([C:9]=23)=[N:7]1)C.CO>O1CCCC1>[N:7]1[NH:6][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[O:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=4[C:8]=1[C:9]=23
Reactant: CCN(CC)CCn1nc2c3c(c(NC(=O)CN(CCOCc4ccccc4)Cc4ccccc4)ccc31)Oc1ccc(O)cc1-2
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc2c(c1)-c1n[nH]c3cccc(c13)O2
Reaction time: 24 h

Procedure:
To a mixture of 2.45 g of N-[2-[2-(diethylamino)-ethyl]-9-hydroxy-2H-[1]benzopyrano[4,3,2-cd]indazol-5-yl]-2-[[2-(phenylmethoxy)ethyl](phenylmethyl)amino]acetamide in 80 ml of dry tetrahydrofuran under argon was added 40 ml of 1M solution of borane tetrahydrofuran complex in tetrahydrofuran. After 24 hours at 50° C., an additional 3 ml of borane tetrahydrofuran complex was added and the reaction continued for another three hours at 50° C. The mixture was poured into 150 ml of methanol, heated under reflux overnight, evaporated to dryness, and the residue of crystallized from diethyl ether to afford 1.36 g of 2-[2-diethylamino)ethyl]-5-[[2-(phenylmethoxy)ethyl](phenylmethyl)amino]ethyl]amino]-2H-[1]benzopyrano[4,3,2-cd]indazol-9-ol.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(=O)=O.[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCCCCOc1ccc2ccccc2c1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCOc2ccc3ccccc3c2)cc1

Procedure:
A solution of 10.0 g. of 6-(2-naphthyloxy)-1-hexanol O-methanesulfonate and 9.7 g. of ethyl 4-aminobenzoate in 50 ml. of hexamethylphosphoramide is heated at 110° C. for 16 hours. The solution is cooled, diluted with water, filtered and the solid washed with ethanol and water to give 7.7 g. of product. Recrystallization from ethanol and once from acetone-hexane gives crystals, m.p. 109°-110° C.
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[C:6]([O:18][CH2:19][CH2:20][CH2:21][Cl:22])=[CH:7][C:8]([N+:15]([O-])=O)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]>[Pt]=S.[C].CO>[CH3:3][O:4][C:5]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]([NH2:15])=[CH:7][C:6]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Agent: S=[Pt]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Reaction time: 8 h
Yield: 97.7 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a balloon containing hydrogen gas were placed 1.01 g (3.29 mmol) of methyl 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-4, 0.2 g of 3 wt. % platinum sulfide/carbon (containing 65.7% water), and 40 mL of methanol. The reaction was carried out at 40° C. for 8 hours. After the reaction was complete, the reaction mixture was filtered. The filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 0.88 g (reaction yield: 98.0%) of methyl 5-methoxy-4-(3-chloropropoxy)anthranilate.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20](C(OCC)=O)[CH2:19][CH2:18]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH:1]([O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)N1CCN(CCOC(c2ccccc2)c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Yield: 94.6 %

Procedure:
To a solution of 4.12 g (11.2 mmol) of the piperazine derivative in methanol (20 ml) and water (10 ml) was added 13.2 g (235 mmol) of of potassium hydroxide, and the mixture was refluxed for 19 hours. Water was added to the reaction mixture and the whole mixture was extracted with n-butanol. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was subjected to Sephadex column chromatography, eluted with methanol, to give 3.15 g (10.6 mmol) of N-(2-benzhydroxyethyl)piperazine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[CH2:17][C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:17][C@@H:18]1[CH2:19][CH2:20][C:21](=[O:23])[O:22]1)(=[O:5])=[O:4]
Reactant: O=C1CC[C@@H](CO)O1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C1CC[C@@H](COS(=O)(=O)C(F)(F)F)O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Trifluoromethanesulfonic anhydride (0.97 g, 3.4 mmol) was added dropwise to a 0° C. solution of (S)-5-(hydroxymethyl)-dihydrofuran-2(3H)-one (0.20 g, 1.7 mmol) and lutidine (0.41 g, 3.8 mmol) in CH2Cl2 (2 mL). The reaction was stirred at 0° C. for 1.5 hours, then diluted with 1:4 EtOAc/hexanes and passed through a plug of silica gel. The volatiles were removed under reduced pressure to yield a yellow oil which was used immediately without purification (0.38 g, 89%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[CH2:28][O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[CH2:45](Br)[C:46]#[CH:47]>CCOCC>[CH3:19][O:18][C:16]([C:12]1[CH:11]=[C:10]2[C:15]([C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[CH2:28][O:29][Si:30]([CH:31]([CH3:32])[CH3:33])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[N:9]2[CH2:47][C:46]#[CH:45])=[CH:14][CH:13]=1)=[O:17]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Reactant: C#CCBr
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCn1c(-c2ccc(OC)cc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To an ice cooled solution of methyl-3-cyclohexyl-2-(4-methoxy-2-{[(triisopropylsilyl) oxy]methyl}phenyl)-1H-indole-6-carboxylate (Example 12, Step 4) in DMF (0.13 M) 60% NaH (2 eq.) was added. After 20 min. propargyl bromide (solution 80% in toluene) (1.5 eq.) was added and the mixture stirred at 0° C. for 1 h, diluted with Et2O, washed with sat aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 20:1). After evaporation of the solvents the product was obtained as a white solid (96%). MS (ES+): 588.7 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:12])=[N:11][C:6]2=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:12])=[N:11][C:6]2=[CH:5][CH:4]=1)(=[O:23])=[O:22]
Reactant: Cc1nc2ccc(CO)nc2s1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(COS(C)(=O)=O)nc2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the alcohol of Step 6 (303 mg, 1.68 mmol) in 17 mL of CH2Cl2 at -40° C., triethylamine (350 μl, 2.5 mmol) and methane-sulfonyl chloride (170 μl, 2.2 mmol) were added and the solution was stirred at -40° C. for 30 min and at 0° C. for 2 hr. Saturated aq. NaHCO3 was added and the product was extracted in CH2C12, dried over Na2SO4, concentrated, and the remaining water was stripped with toluene twice.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(F)cc1
Product: COc1ccc(-c2nc3cc(-c4ccc(F)cc4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-fluorophenylboronic acid (120 mg, 0.86 mmol) the subtitle compound was obtained, (135 mg, 65%). 1H NMR (DMSO) δ 8.64(d, 1H), 8.45(dd, 1H), 8.05(d, 1H), 7.87(d, 2H), 7.78(dd, 1H), 7.72(dd, 1H), 7.62(d, 2H), 7.33(t, 1H), 4.08(s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[O:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccc1Oc1ccccc1
Reactant: C1CNCCN1
Product: c1ccc(Oc2ccccc2N2CCNCC2)cc1

Procedure:
A mixture of phenylboronic acid (5.12 g, 42 mmol), 2-bromophenol (3.55 g, 21 mmol), Cu(OAc)2 (7.63 g, 42 mmol), pyridine (8 ml, 103 mmol) and 4 Å molecular sieves (2.1 g) in CH2Cl2 was stirred at r.t. overnight. The mixture was diluted with CH2Cl2, filtered through celite, washed with 1M NaOH, brine and dried. Removal of solvent gave 1-bromo-2-phenoxybenzene, crystals (1.40 g, 27%). LRMS (ESI+): 248 (M+1). 1-Bromo-2-phenoxybenzene was coupled to piperazine using the Buchwald chemistry described in preparation 1A to afford the title compound. LRMS (ESI+) 255 (M+1)
Reaction SMILES: [NH2:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:14]([OH:17])(=[O:16])C>>[CH2:3]([O:17][C:14]([O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@H:2]([C:11]([OH:13])=[O:12])[NH2:1])=[CH:9][CH:8]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CC(=O)O
Product: N[C@H](Cc1ccc(OC(=O)OCc2ccccc2)cc1)C(=O)O

Procedure:
This compound was prepared from D-tyrosine (1.02 g) in the same manner as the L-isomer as described by Overell and Petrow, J. Chem. Soc. 232 (1955); yield, 0.73 g (40%); mp 208°-210° decn; tlc (BAW) Ff 0.55; [α]D24 +9.1 (c 2.14, 80% acetic acid).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34]([OH:36])=O.CCN(C(C)C)C(C)C.[CH:46]1([C:52]2[CH:53]=[CH:54][C:55]([O:72][CH3:73])=[C:56]([C:58]3[N:59]=[C:60]([NH:63][C:64]([CH:66]4[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]4)=[O:65])[S:61][CH:62]=3)[CH:57]=2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(#N)C>[CH:46]1([C:52]2[CH:53]=[CH:54][C:55]([O:72][CH3:73])=[C:56]([C:58]3[N:59]=[C:60]([NH:63][C:64]([CH:66]4[CH2:67][CH2:68][N:69]([C:34]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][N:28]=5)=[O:36])[CH2:70][CH2:71]4)=[O:65])[S:61][CH:62]=3)[CH:57]=2)[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)C2CCNCC2)n1
Reactant: O=C(O)c1cnccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)C2CCN(C(=O)c3cnccn3)CC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
0.32 g of BOP, 0.08 g of pyrazinecarboxylic acid and then 0.37 mL of DIPEA are added, at a temperature of 0° C., to a solution of 0.25 g of the compound prepared in step 1.2 in 3 mL of acetonitrile. The medium is stirred at room temperature for 12 hours and then concentrated. The medium is taken up in EtOAc and washed 3 times with 10% Na2CO3 solution and then with saturated NaCl solution. After drying over MgSO4, the solution is concentrated and then purified by flash chromatography to give 0.23 g of a dark yellow solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:21][CH:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH:22]([CH3:26])[C:23]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a mixture of tert-butyl piperazine-1-carboxylate (2.0 g, 11 mmol) in methylene chloride (20 mL) was added triethylamine (3.0 mL, 21 mmol) followed by 2-chloropropanoyl chloride (1.5 g, 12 mmol) drop-wise at 0° C. The reaction was stirred for 1 h, quenched with water, and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried over magnesium sulfate and then evaporated to dryness to provide the crude product (3 g, 101%). LCMS calculated for C8H14ClN2O3 (M-Bu+H)+: m/z=221.1; Found: 221.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:5]2=[N:6][CH:7]=1.[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O.O.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]>[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[C:4]3[N:10]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[S:8][C:5]3=[N:6][CH:7]=2)=[CH:28][CH:29]=1)=[O:20]
Reactant: CS(=O)(=O)NCc1nc2cc(Br)cnc2s1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)NCc1nc2cc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc3)cnc2s1
Temperature: 70 °C
Yield: 25.2 %

Procedure:
A mixture of N-((6-bromothiazolo[5,4-b]pyridin-2-yl)methyl)methanesulfonamide (236 mg, 0.732 mmol), 2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (300 mg, 0.0.732 mmol) and tris(2-furyl)phosphine (34 mg, 0.146 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (68 mg, 0.0732 mmol) in dimethylformamide (3 mL) is heated at 70° C. for 5 hours under nitrogen. The mixture is then cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). Extracts are dried over Na2SO4 and concentrated to get crude product. Obtained product purified by HPLC to give the title compound (90 mg): 1HNMR (DMSO-d6): 3.07 (s, 3H), 4.27-4.39 (m, 1.5H), 4.40-4.48 (m, 0.5H), 4.52-4.60 (m, 0.5H), 4.64-4.71 (m, 2.5H) 4.88-4.94 (m, 1H), 6.22 (t, 1H), 7.50 (d, 2H), 7.83 (d, 2H), 8.22-8.33 (m, 1H), 8.62 (bs, 1H), 8.85 (d, 1H), 8.94 (s, 1H). m/z (Cl) M+H 489.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([OH:15])[CH:13]=[CH2:14]>>[CH2:12]([O:15][C:4](=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11])[CH:13]=[CH2:14]
Reactant: C=CCO
Reactant: O=C1OC(=O)c2ccccc21
Product: C=CCOC(=O)c1ccccc1C(=O)O
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A 100-mL three-necked round-bottom flask was fitted with a reflux condenser and, in a nitrogen atmosphere, the flask was charged with phthalic anhydride (4.0 g, 13.5 mmol) and allyl alcohol (4.58 mL), and the contents were stirred at 90° C. for 30 minutes. The unreacted allyl alcohol fraction was distilled off under reduced pressure to give phthalic acid monoallyl ester (yield 5.66 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:20])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)COC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CC(C)COC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.053 mMol) isobutyl chloroformate, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[O-].[K+]>CO>[C:11]1([S:17][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:1]([OH:3])=[O:2])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1OCc2ccccc21
Reactant: Sc1ccccc1
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)c1ccccc1CSc1ccccc1
Yield: 78 %

Procedure:
A mixture of 67.1 gm of phthalide, 51.3 ml of thiophenol, 35.1 gm of potassium methylate and 250 ml of methanol was refluxed. Subsequently, the obtained 2-(phenylmercapto-methyl) -benzoic acid (yield: 78% of theory, m.p. 108°-110° C.) was esterified with methanol/thionylchloride by standing at -40° C. After standing overnight at room temperature, methyl 2-(phenylmercapto-methyl)-benzoate (yield: 89% of theory, b.p. 145° C. at 0.07 mm Hg) was obtained, which was converted into 2-(phenylmercapto-methyl)-phenyl carbinol (yield: 97% of theory, m.p. 64°-65° C.) by reduction with lithium aluminum hydride in diethyl ether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:12]=2[OH:14])[NH:7][CH:6]([CH3:23])[CH2:5]1.C=O.[C:26]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[OH:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:12]=2[OH:14])[N:7]([CH3:26])[CH:6]([CH3:23])[CH2:5]1
Reactant: CCCCSCCCc1cc(O)c2c(c1)NC(C)CC2CCO
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCCSCCCc1cc(O)c2c(c1)N(C)C(C)CC2CCO

Procedure:
To a stirred solution of dl-4-(2-hydroxyethyl)-5-hydroxy-2-methyl-7-(4-thiaoctyl)-1,2,3,4-tetrahydroquinoline (337 mg, 1.0 mmole) in 5 ml acetonitrile cooled to 15° C. is added 0.5 ml aqueous formaldehyde and 100 mg sodium cyanoborohydride. Acetic acid is added to maintain a neutral pH unit the reaction is complete. The reaction mixture is partitioned between water and ethyl ether, the organic phase dried (MgSO4) and evaporated to afford the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[C:10]1[N:14]=[C:13]([C:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C4CCCCO4)=[CH:23][CH:22]=3)[S:17][CH:16]=2)[N:12]([CH3:34])[N:11]=1.O>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[C:10]1[N:14]=[C:13]([C:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[S:17][CH:16]=2)[N:12]([CH3:34])[N:11]=1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)csc1-c1ccc(OC2CCCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)csc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
Dilute hydrochloric acid (4 N, 2.5 mL) was added to a suspension of 3-(2-chloro-6-fluorophenyl)-5-{4-methyl-5-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]thien-3-yl}-1-methyl-1H-1,2,4-triazole (0.62 g, 1.3 mmol) in tetrahydrofuran (2.5 mL), stirred at room temperature for 30 minutes, poured into water (20 mL) and extracted with ether (3×20 mL). The combined ethereal extracts were washed with water (100 mL) and brine (50 mL), dried over magnesium sulphate and concentrated under reduced pressure to leave the desired product (0.49 g, 96%) as a white solid. 1H NMR (CDCl3) and mass spectrometry data indicated this material to be free of impurities and to be comparable to authentic material prepared according to that in Example K.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:3]=1[CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[Li]CCCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:2]([B:27]([OH:32])[OH:28])=[C:3]([CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
[(2-bromo-5-methoxybenzyl)oxy](triisopropyl)silane (1 eq) was dissolved in anhydrous THF (0.43M solution) and the solution was cooled to −78° C. A solution of n-BuLi (1.6M in hexanes, 1.05 eq) was added and the resulting mixture was stirred for 1 h at −78° C. Then triisopropyl borate (50% in THF, 1.3 eq) was added dropwise and the mixture was allowed to warm to RT overnight. 1N HCl was added and the resulting mixture was stirred at RT for 30 min. THF was removed in vacuo and replaced with Et2O. The organic phase was washed with water and with brine, then dried over Na2SO4 and evaporated in vacuo. The product was obtained as a colourless oil (64% yield, 65% pure) which was used without further purification in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1Cl.[CH3:12]O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:4]=[C:3]([CH3:12])[C:2]([NH2:1])=[C:9]([I:10])[CH:8]=1
Reactant: N#Cc1cc(Cl)c(N)c(I)c1
Reactant: CO
Solvent: C1CCOC1
Product: Cc1cc(CN)cc(I)c1N
Reaction time: 12 h

Procedure:
4-Amino-3-chloro-5-iodobenzonitrile (65.2 mg, 0.23 mmol) was dissolved in THF at 0° C. After Borane-THF complex (4 eq, 0.94 mmol, 0.94 ml) was slowly added into the reaction mixture, A reaction temperature was heated to reflux. The reaction mixture was stirred for 12 hr with reflux. After confirming the completion of the reaction, MeOH was added. The mixture was stirred for 4 hr. The reaction solvent was removed in vacuo. A residue was extracted with Ethyl acetate, washed with H2O and brine, dried with Na2SO4 and concentrated in vacuo to yield 4-Aminomethyl-2-iodo-6-methyl-phenylamine (19.4 mg).