Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[C:36]([O:40][C:41](=[O:47])[NH:42][CH:43]1[CH2:46][NH:45][CH2:44]1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41](=[O:47])[NH:42][CH:43]1[CH2:46][N:45]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[C:5]3[N:9]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:10]([C:12]4[C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=5)[N:14]([CH3:25])[CH:13]=4)=[CH:11][C:4]=23)[CH2:44]1)([CH3:39])([CH3:37])[CH3:38].[C:36]([O:40][C:41](=[O:47])[NH:42][CH:43]1[CH2:46][N:45]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:9][C:10]([C:12]4[C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=5)[N:14]([CH3:25])[CH:13]=4)=[CH:11][C:4]=23)[CH2:44]1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: COc1cc2c(-c3cc4c(CCl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Product: COc1cc2c(-c3cc4c(CN5CC(NC(=O)OC(C)(C)C)C5)ccnc4[nH]3)cn(C)c2cc1OC
Product: COc1cc2c(-c3cc4c(CN5CC(NC(=O)OC(C)(C)C)C5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Yield: 200.1 %

Procedure:
{1-[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-yl}carbamic acid tert-butyl ester is prepared as described in Example 200b starting with 0.14 g of 4-chloromethyl-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.118 g of azetidin-3-ylcarbamic acid tert-butyl ester instead of the piperid-4-ol used in Example 200b. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 95/5 by volume as eluent), 0.135 g of {1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-yl}carbamic acid tert-butyl ester is obtained, the characteristics of which are as follows:
Reaction SMILES: C(O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C([N:40]([CH2:43]C)CC)C.CC[O:47]CC>C1(C)C=CC=CC=1>[CH2:2]([N:40]=[C:43]=[O:47])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCOCC
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCN=C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of toluene is dissolved 5.68 g of stearic acid, followed by addition of 5.5 g of diphenyl phosphororazidate ##STR19## hereinafter DPPA] and 3.0 ml of triethylamine. The mixture is stirred at room temperature for 2 hours. The reaction mixture is cooled, 100 ml of ether is added and the ether layer is washed with ice-water. The organic layer is taken, dehydrated with a dehydrating agent and refluxed for 2 hours, whereby 5.3 g of the above-indicated compound is obtained as colorless oil.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([C:6]([CH2:8][CH2:9][CH2:10]Cl)=[O:7])[S:3][CH:2]=1.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][NH:13]1>>[O:7]=[C:6]([C:4]1[S:3][CH:2]=[CH:1][CH:5]=1)[CH2:8][CH2:9][CH2:10][N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(CCCCl)c1cccs1
Product: O=C(CCCN1CCc2ccccc2C1)c1cccs1
Yield: 58 %

Procedure:
Prepared in standard fashion from commercially available 4-chloro-2′-butyrothienone and 1,2,3,4-tetrahydroisoquinoline. Purified by flash chromatography, eluting with 1:1 EtOAc/hexane to provide 17A (58% yield) as a yellow oil. 1H NMR(300 MHz, CDCl3, δ): 7.72-7.70 (m, 1H), 7.60-7.58 (m, 1H), 7.15-6.98 (m, 5H), 3.62 (s, 2H), 3.01 (t, 2H, J=7 Hz), 2.87 (t, 2H, J=6 Hz), 2.72 (t, 2H, J=6 Hz), 2.59 (t, 2H, J=7 Hz), 2.10-2.00 (m, 2H). 13C NMR(300 MHz, CDCl3, δ): 193.10, 144.56, 134.92, 134.43, 133.34, 131.79, 128.64, 128.05, 126.59, 126.08, 125.58, 57.37, 56.10, 50.83, 37.01, 29.19, 22.14. . IR(KBr, cm−1): 1662 (s). UV (MeOH): max 282 nm, ε 260. MS(CI, NH3) m/e 286 (base, M+H ). HRMS(CI, NH3) m/e Calc'd for (M+H+): 286.1266. Found: 286.1259.
Reaction SMILES: N[C:2]1[C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.N.Cl.CO>O1CCCC1.N1C=CC=CC=1>[NH:8]1[C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=[N:9]1
Reactant: Nc1cccc2nn[nH]c12
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CO
Solvent: c1ccncc1
Product: c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the above acid chloride (ca. 0.02M) in tetrahydrofuran (10 ml) was added over 8 minutes to a stirred solution of 7-aminobenzotriazole (2.5 g, 0.019M) in pyridine (20 ml). The mixture was stirred at room temperature for 4 hours, then 0.88M ammonia (0.5 ml) was added and stirring was continued for another 20 minutes. The mixture was poured into ice/water (200 ml) to give an oil which soon solidified. 10M Hydrochloric acid (25 ml) was added and the acidified mixture was stirred for 5 minutes before the resulting pink solid was filtered off, washed with water and dried, 5.8 g. The solid was added to methanol (25 ml) and the suspension was stirred at room temperature for 1 hour. Filtration of the mixture resulted in removal of most of the colour from the solid, which was further washed with methanol and dried, 4.3 g. The solid was heated briefly on a steam-bath with tetrahydrofuran (50 ml) to give a cloudy solution. This was cooled and filtered through Kieselguhr and the filtrate was concentrated under reduced pressure to leave an off-white solid. Methanol (25 ml) was added and the mixture was stirred at room temperature for 2 hours, then the resulting white solid was filtered off, washed with methanol and dried to give B1-1, 15 g (52%). The positive and negative ion electrospray mass spectra were consistent with the structure of the required product. LCMS indicated purity of >98%, which was also supported by the 1H-nmr spectrum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH2:20](I)[CH:21]=[CH2:22]>C(O)C.CCOCC>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1)[CH:21]=[CH2:20]
Reactant: C=CCI
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: C=CCOc1cccc([C@@H]2C[C@H]2CNC(=O)CCC)c1
Reaction time: 18 h
Yield: 34.4 %

Procedure:
To a rapidly stirred solution of (trans)-N-[[2-(3-hydroxyphenyl)cyclopropyl]methyl] butanamide (0.8 g, 3.4 mmol) and KOH (210 mg, 3.74 mmol) in ethanol (15 mL) was added allyl iodide (622 mg, 3.7 mmol). After stirring for 18 h, the suspension was diluted with Et2O (100 mL), and washed with H2O, 2N NaOH, brine, dried (K2CO3), and concentrated to a give a crude residue. The resulting material was purified by chromatography (silica gel, 40 % EtOAc/hexane) to afford 320 mg (34%) of the title compound: 1H NMR (300 MHz, CDCl3) δ0.70-0.94 (m, 5H), 1.12-1.32 (m, 1H), 1.58-1.84 (m, 3H), 2.20 (t, J=6.0 Hz, 2H), 3.15-3.36 (m, 2H), 4.48 (d, J=5.6 Hz, 2H), 5.24 (d, J=10.0 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 5.56 (br s, 1H), 5.96-6.07 (m, 1H), 6.57-6.70 (m, 3H), 7.13 (t, J=7.2 Hz, 1H); IR (NaCl Film) 3296, 2962, 1644, 1607, 1548, 1494 cm-1 ; MS m/e 273; Analysis calc'd for C17H23NO2 0.20(H2O): C, 73.72; H, 8.52; N, 5.06; found: C, 73.77; H, 8.63; N, 5.00.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:40]1[CH2:44][CH2:43][C@@H:42]([C:45]2[O:49][N:48]=[C:47]([C:50]3[S:51][CH:52]=[CH:53][N:54]=3)[N:46]=2)[CH2:41]1>CN(C=O)C>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([N:40]1[CH2:44][CH2:43][C@@H:42]([C:45]2[O:49][N:48]=[C:47]([C:50]3[S:51][CH:52]=[CH:53][N:54]=3)[N:46]=2)[CH2:41]1)=[O:6]
Reactant: c1csc(-c2noc([C@@H]3CCNC3)n2)n1
Reactant: O=C(O)CCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCC(F)(F)F)N1CC[C@@H](c2nc(-c3nccs3)no2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)—N—Boc-pyrrolidine-3-carboxylic acid (700 mg, 3.25 mmol, 1.1 equiv), HBTU (1.23 g, 1.1 equiv) and DIEA (1.53 mL, 3 equiv) were dissolved in DMF (15 mL). The solution was stirred 5 min and then 1,3-thiazole-2-amidoxime (5a) (422 mg, 2.95 mmol, 1 equiv) was added. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with saturated aqueous NaHCO3, once with brine, then dried over MgSO4 and evaporated under reduced pressure. The residue was dissolved in 15 mL of DMF and then heated at 110° C. for 7 h. The solvent was removed under vacuum and the residue was dissolved in AcOEt. The organic layer was washed once with HCl 1N, once with saturated aqueous NaHCO3 and once with brine, then dried over MgSO4 and evaporated under reduced pressure. The obtained product was used in the next step without further purification. Boc intermediate was dissolved in dioxane (10 mL) and HCl 4N solution in dioxane (6 mL) was added. The reaction mixture was stirred overnight at room temperature and then the product was recovered by filtration and washed with petroleum ether to give 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (yield 66% over two steps). 4,4,4-trifluorobutyric acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.4 equiv) and DIEA (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (0.62 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Beige powder; Yield 33%; 1H NMR (CDCl3) δ 8.02-8.00 (m, 1H), 7.57-7.60 (m, 1H), 3.89-4.03 (m, 2H), 3.69-3.87 (m, 2H), 3.53-3.65 (m, 1H), 2.38-2.55 (m, 6H); 13C NMR (CDCl3) cis/trans isomer mixture (60 isomer A/40 isomer B); isomer A δ 180.31, 168.50, 163.98, 153.53, 144.99, 126.94 (q, J=276 Hz), 122.87, 49.24, 45.52, 35.03, 29.05 (q, J=29 Hz), 28.86, 27.07 (q, J=3 Hz); isomer B δ 179.84, 168.31, 163.98, 153.38, 144.94, 126.92 (q, J=276 Hz), 122.81, 49.43, 45.25, 36.82, 30.28, 29.05 (q, J=29 Hz), 27.24 (q, J=3 Hz). tR LCMS 4.6 min. Purity >99%; MS [M+H]+ m/z 347.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]#[N:22])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:4]([CH3:23])[CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[NH:26][N:25]=[N:24][N:22]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1nc(C#N)sc1-c1ccc(Cl)cc1C
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Product: Cc1cc(Cl)ccc1-c1nc(-c2nnn[nH]2)sc1-c1ccc(Cl)cc1C
Temperature: 150 °C
Yield: 71 %

Procedure:
A round-bottomed flask was charged with 4,5-bis(4-chloro-2-methylphenyl)thiazole-2-carbonitrile (150 mg, 0.42 mmol), zinc bromide (189 mg, 0.84 mmol) and sodium azide (45.5 mg, 0.84 mmol). After degassed, DMF (3 mL) was added. The reaction mixture was heated to 150° C. overnight. After cooled to rt, the reaction was quenched with 30 mL of 0.1 N aqueous HCl, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc:AcOH=30:10:1). 120 mg of product was obtained as a white solid, 1H NMR (DMSO, 500 MHz) δ 7.93 (d, J=8.41 Hz, 1H), 7.57 (d, J=1.90 Hz, 1H), 7.49-7.44 (m, 2H), 7.33-7.28 (m, 2H), 2.63 (s, 3H), 2.18 (s, 3H); 13C NMR (DMSO, 125 MHz) δ 166.07, 153.61, 139.50, 138.74, 134.92, 133.48, 132.53, 131.87, 131.42, 130.27, 129.98, 126.64, 125.67, 21.13, 19.51.
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[C:16](C)=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1.[Cl:21]N1C(=O)CCC1=O.[C:29]([Cl:33])(Cl)(Cl)Cl>>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[C:16]([CH3:17])=[C:29]([Cl:33])[C:18]([Cl:21])=[N:19][C:5]2=3)[CH2:3][CH2:2]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Product: Cc1c(Cl)c(Cl)nc2c1NC(=O)c1cccnc1N2C1CC1
Reaction time: 4 h

Procedure:
A mixture of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.5 g) and N-chlorosuccinimide (0.5 g) in carbon tetrachloride (50 mL) was heated under reflux for 6 hours. An additional 0.25 g of N-chlorosuccinimide was added and heating under reflux was continued for 4 hrs more. The mixture was filtered and the solvent was evaporated. The residue was fractionated over silica gel with ethyl acetate/hexane to give the title compound which crystallized from ethyl acetate/ethanol, m.p.>290° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][C@@H:10]([OH:12])[CH2:9][NH:8]2)=O)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]1([NH:4][CH2:5][C@@H:7]2[NH:8][CH2:9][C@H:10]([OH:12])[CH2:11]2)[CH2:2][CH2:3]1
Reactant: O=C(NC1CC1)[C@H]1C[C@@H](O)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@H]1CN[C@@H](CNC2CC2)C1
Yield: 36.3 %

Procedure:
1H NMR (400 MHz, DMSO-d6)δ 4.32 (m, 1H), 4.1 (m, 1H), 3.2 (m 2H), 2.67 (m, 1H), 2.35 (m, 1H), 1.85 (m, 1H), 0.67 (m, 2H), 0.45 (m, 2H). [486] (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide (3 g) was reduced using LAH (2 g) in THF (150 mL) to give 1 g of (3R,5R)-5-cyclopropylaminomethyl-pyrrolidin-3-ol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Reactant: C1COCCN1
Product: O=C(NCc1nccnc1Cl)C1CCC(N2CCOCC2)CC1

Procedure:
According to the procedure described in example 7 step 7a N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (1 g) and morpholine (0.44 mL) gave after work-up N-((3-chloropyrazin-2-yl)methyl)-4-morpholinocyclohexanecarboxamide (1.28 g). This crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=[C:4](SC)[N:3]=1.O[O:32][S:33]([O-:35])=O.[K+].[C:37](#N)C>O.CCOC(C)=O>[CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH3:12])[N:5]=[C:4]([S:33]([CH3:37])(=[O:35])=[O:32])[N:3]=1
Reactant: CSc1nc(C)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)n1
Reactant: CC#N
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(S(C)(=O)=O)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of (S)-4-methyl-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (197 mg, 0.465 mmol) in acetonitrile (2 mL) and H2O (2 mL) was cooled to 0° C. Oxone® (715 mg, 1.163 mmol) was added to give an orange suspension. The reaction mixture was stirred at 0° C. for 30 minutes, warmed to room temperature, and stirred for an additional 3 hours. The reaction mixture was subsequently diluted with EtOAc and washed with H2O (3×5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound, which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](I)=[C:16]([F:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1](=[O:3])[CH3:2])=[C:16]([F:21])[CH:15]=1
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: Fc1cc(Cl)ccc1I
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
Product: CC(=O)c1ccccc1-c1ccc(Cl)cc1F
Temperature: 85 °C
Yield: 53.7 %

Procedure:
2-Acetylphenylboronic acid (5 g, 30.5 mmol) and 4-chloro-2-fluoroiodobenzene (8.6 g, 33.5 mmol) were dissolved in a toluene/ethanol mixture (6:1, 175 mL). An aqueous solution of potassium carbonate (2 M, 60 mL) and tetrakis(triphenylphosphine)palladium (0) (1.06 g, 0.91 mmol) were added to the solution and the entire mixture was degassed using vacuum and stirring with intermittent nitrogen purge. The mixture was heated at 85° C. with stirring for 14 hours. The mixture was allowed to cool and then water was added. The organic phase was separated from the aqueous phase and the aqueous phase was extracted with ethyl acetate (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. The crude oil was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-20% methyl tert-butyl ether in hexane, to afford the desired product (4.07 g, 54%) as a yellow oil;
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[F:9][C:10]([F:21])([F:20])[C:11]1[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[F:21][C:10]([F:9])([F:20])[C:11]1[C:16]([C:17]([O:19][CH3:1])=[O:18])=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
6.7 g (48.6 mmoles) of anhydrous potassium carbonate and 6.9 g (48.6 mmoles) of methyl iodide were added to a solution of 4.6 g (24.1 mmoles) of 4-trifluoromethylnicotinic acid dissolved in 70 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 2.77 g (yield: 56.1%) of methyl 4-trifluoromethylnicotinate as a yellow oily substance.
Reaction SMILES: [C:1]([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=1)[CH2:11][C@H:12]([C:14]([OH:16])=[O:15])[NH2:13].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:17](=[CH:18][CH:19]=1)[CH2:1][N:13]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@@H:12]([C:14]([OH:16])=[O:15])[CH2:11]2
Reactant: CCOC(=O)Cl
Reactant: O=C([O-])[O-]
Reactant: N[C@H](Cc1cccc(Cl)c1)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)N1Cc2ccc(Cl)cc2C[C@@H]1C(=O)O
Reaction time: 8 h

Procedure:
Na2CO3 (2.12 g, 20.04 mmol) was added to a suspension of 3-chloro-D-phenylalanine 9 (2.6 g, 10.02 mmol) in MeOH/H2O (8.3 mL/8.3 mL) at room temperature. Ethyl chloroformate (1.44 mL, 15.03 mmol) was added drop wise over 20 min via syringe pump and the reaction was stirred overnight. The reaction mixture was washed with Et2O (1×15 mL) and the aqueous layer was acidified to pH ˜5 with 2 M HCl (aq). The aqueous layer was extracted with EtOAc (2×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to obtain the ethyl carbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH3:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)(=[O:11])=[O:10])=[CH:5][C:4]=1[N+:26]([O-])=O.C1COCC1>CO.[Pd]>[NH2:26][C:4]1[CH:5]=[C:6]([S:9]([N:12]([CH3:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(S(=O)(=O)N(C)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(C)c2cc(OC)c(OC)c(OC)c2)cc1N
Reaction time: 4 h

Procedure:
A solution of Example 52A (00 mg) in methanol:THF (1 mL: 1 mL) was treated with 10% palladium on carbon, stirred under hydrogen (1 atm) for 4 hours, filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2% methanol/dichloromethane to provide 31 mg of the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17]C)=[O:16])[N:5]=2.C(N(CC)CC)C.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>O1CCCC1.O>[CH:29]1([C:32]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([OH:17])=[O:16])[N:5]=3)=[O:33])[CH2:31][CH2:30]1
Reactant: COC(=O)c1cccc(Oc2ccc3nc(N)sc3n2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Yield: 79 %

Procedure:
To a solution of methyl 3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]benzoate (4.20 g, 13.9 mmol) and triethylamine (3.47 μL, 25.1 mmol) in tetrahydrofuran (40 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (1.52 mL, 16.7 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethanol (50 mL). 8N Aqueous sodium hydroxide solution (7 mL) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was adjusted to pH 4 with 6N hydrochloric acid, and the precipitated solid was collected by filtration and washed with water to give the title compound (3.90 g, 79%) as a white solid.