Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[CH3:26][C@@H:19]([O:18][C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]([OH:27])=[O:8])=[CH:15][CH:14]=1)=[O:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC[C@@H](C)OC(=O)c1ccc(C(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(C(=O)O)cc1
Yield: 99.6 %

Procedure:
Then, 0.12 g of 5% palladium/carbon and 30 ml of a tetrahydrofuran solution containing 1.21 g of 4-((R)-1-methylheptyloxycarbonyl)benzoic acid benzyl ester were stirred overnight at room temperature in a stream of hydrogen to decompose a benzyl protective group by hydrogenation. 5% palladium/carbon was removed using Celite as a filter aid, and the filtrate was concentrated. The concentrate obtained was purified by column chromatography to obtain 0.91 g of 4-((R)-1-methylheptyloxycarbonyl)benzoic acid as a colorless liquid (gradually crystallized) (isolated yield: 99%).
Reaction SMILES: C[O-].[Na+].[N:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[C:5]=[S:6].[NH2:13][C:14]#[N:15].Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CO>[CH3:21][O:20][C:18]([C:17]1[S:6][C:5]([NH:4][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:15][C:14]=1[NH2:13])=[O:19]
Reactant: S=C=Nc1ccccc1
Reactant: N#CN
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(Nc2ccccc2)nc1N
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A 0.5 M solution of sodium methoxide in methanol (44.4 mL, 22.19 mmol) was added dropwise to a suspension of isothiocyanato-benzene Compound 3a (2.0 g, 14.79 mmol) and NH2CN (0.684 g, 16.27 mmol) in methanol (50 mL) at 0° C. The mixture was stirred at r.t. until Compound 3a was no longer detected (about 3 hrs). Methyl chloroacetate (1.56 mL, 17.75 mmol) was added at r.t. and the mixture was warmed to 50-60° C. and stirred at 50-60° C. for about 3 hrs, then stirred at r.t. overnight. The mixture was evaporated to dryness in vacuo and the resultant solid was thoroughly washed with water, methylene chloride and a small amount of methanol to give 4-amino-2-phenylamino-thiazole-5-carboxylic acid methyl ester Compound 3b (1.12 g, 60%) as a yellow powder. MS 250 (M+H+), 248 (M−H+)
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH:14][S:15]([CH2:18][CH:19](O)[CH2:20][CH2:21][CH3:22])(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCCC1>[C:10]([NH:14][S:15]([CH2:18][CH:19]([O:8][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH2:21][CH3:22])(=[O:17])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(O)c1ccccc1
Reactant: CCCC(O)CS(=O)(=O)NC(C)(C)C
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: C1CCOC1
Product: CCCC(CS(=O)(=O)NC(C)(C)C)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.7 %

Procedure:
Under nitrogen atmosphere, benzoic acid (92.8 g) was added gradually to a mixture of N,N′-carbonyldiimidazole (123.3 g) and tetrahydrofuran (500 ml) taking 10 minutes at room temperature. After stirring for 1 hour at room temperature, a solution of N-t-butyl-2-hydroxy-1-pentanesulfonamide (84.9 g) in tetrahydrofuran (300 ml) was added dropwise thereto taking 15 minutes. Then, a solution of diazabicycloundecene (57.9 g) in tetrahydrofuran (200 ml) was added dropwise thereto taking 35 minutes and the resulting solution was stirred for 17 hours at room temperature. The reaction mixture was decanted to ice-water, made acidic by adding dilute hydrochloric acid, and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over sodium sulfate, and concentrated under reduced pressure to obtain N-t-butyl-2-benzoyloxy-1-pentanesulfonamide (132.8 g) as yellowish brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:26][CH2:27][C@@H:28]([OH:30])[CH3:29]>>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:26][CH2:27][C@@H:28]([OH:30])[CH3:29])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCl)ccc1Cl
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNCCOc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: Cl

Procedure:
Prepared according to the method of Example 4 using 2-chloro-5-(2-chloroethoxy)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.17 g, Example 11a) and (S)-1-amino-2-propanol (0.11 ml). The reaction mixture was partitioned between ethyl acetate and sodium hydrogencarbonate solution, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by RPHPLC (eluting with 25-95% MeCN in 0.1% AcONH4 aqueous) to give the title compound as the acetate salt. This was converted to the hydrochloride salt by stirring with 4M HCl in dioxane and concentration under reduced pressure. Recrystalisation from isohexane/isopropanol gave the title compound as a solid (0.05 g).
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([O:19][CH3:20])[CH:9]=2)([CH3:3])[CH3:2].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:6]2[C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:29])=[N:14][C:13]3[C:8](=[CH:9][C:10]([O:19][CH3:20])=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=3)[N:7]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cc2nc(N(C)C(C)C)c(OS(=O)(=O)C(F)(F)F)nc2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc2nc(N(C)C(C)C)c(-c3ccc(F)cc3)nc2cc1OC
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-7-methoxy-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (2.5 g, crude) in dioxane (5.0 mL) and water (3 drops) was added (4-fluorophenyl)boronic acid (2.40 g, 17.15 mmol), Pd(PPh3)4 (320 mg, 0.28 mmol), and K3PO4 (3.58 g, 16.87 mmol) with stirring for 1.5 h at 95° C. under an atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-(isopropyl(methyl)amino)-7-methoxyquinoxaline-6-carboxylate as a light yellow solid (0.9 g, 36% 2 steps).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)#[CH:18]>>[CH3:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=[CH:23][CH:22]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1cccc(C)c1
Product: Cc1cccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Yield: 59.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 3-ethynyltoluene (0.08 mL, 0.65 mmol) to provide 256 (80 mg, 60% yield) as a tan solid. LC-MS (M+H=311 obsd.=311).
Reaction SMILES: F[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.C([OH:25])C>>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[NH+:12]([O-:25])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1ccc2ccccc2c1
Reactant: CCO
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Product: O=[N+]([O-])c1ccncc1[NH+]([O-])c1ccc2ccccc2c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To 150 ml of ethanol were added 3-fluoro-4-nitropyridine-N-oxide (7.0 g) and 2-aminonaphthalene (6.6 g) and the mixture was heated to 70° C. and stirred for one hour. The mixture was cooled and filtered and the solid collected to yield a solid (11.5 g). A 2.5 g portion of this material was triturated with methanol to yield a solid, 2.5 g, m.p. 222°-224° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[C:17]1([N:23]2[C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:11]1([C:8]2[N:6]3[CH:7]=[C:2]([C:27]4[N:23]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:24]=[CH:25][CH:26]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Reactant: Brc1ccc2ncc(-c3ccccc3)n2c1
Product: c1ccc(-c2cnc3ccc(-c4ccnn4-c4ccccc4)cn23)cc1

Procedure:
The title compound, off-white solid (48 mg, 39%), MS (ISP) m/z=337.5 [(M+H)+], mp 139° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-phenyl-imidazo[1,2-a]pyridine (intermediate G) (0.1 g, 0.366 mmol) and 1-phenyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate D) (0.12 g, 0.44 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:26])=[C:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:27]([O:29][C:30](=[O:42])[C:31]([O:34][C:35]1[CH:40]=[CH:39][C:38]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:9][C:10]=2[CH3:26])=[CH:37][CH:36]=1)([CH3:33])[CH3:32])[CH3:28]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
Yield: 44 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethyl ester, 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (American Home Products U.S. Pat. No. 3,795,691) (7.06 g, 31.5 mmol) and Cs2CO3 (13.3 g, 41.0 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between ethyl acetate (250 mL) and H2O (250 mL), and the aqueous phase extracted with ethyl acetate (2×100 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, hexanes to 10% ethyl acetate/hexanes) to provide 2-(4-{2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (6.81 g, 44%) as a off-white solid. Rf=0.39 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ8.11 (t, J=1.6 Hz, 1H), 7.89-7.86 (m, 1H), 7.49 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 6.80-6.72 (m, 4H), 4.20 (q, J=7.2 Hz, 2H), 4.15 (t, J=6.6 Hz, 2H), 2.92 (t, J=6.6 Hz, 2H), 2.34 (s, 3H), 1.49 (s, 6H), 1.24 (t, J=7.2 Hz, 3H); MS (EI) 510.1 (M+Na)+, 488.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][N:10]=[CH:9]1)[CH3:2].[Cl:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[Cl-:19].[CH2:20]([N+:10]1[CH2:11][CH2:12][N:8]([CH2:7][CH2:6][CH2:5][Si:4]([O:13][CH2:14][CH3:15])([O:16][CH2:17][CH3:18])[O:3][CH2:1][CH3:2])[CH:9]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCCl
Reactant: CCO[Si](CCCN1C=NCC1)(OCC)OCC
Product: CCCC[N+]1=CN(CCC[Si](OCC)(OCC)OCC)CC1
Product: [Cl-]
Temperature: 78 °C
Yield: 99 %

Procedure:
A mixture of N-(3-triethoxysilylpropyl)-4,5-dihydroimidazol (13.7 g, 0.05 mol) and 1-chlorobutane (13.9 g, 0.15 mol) were refluxed at 78° C. for 21 hrs. The reaction mixture was cooled to room temperature and the volatiles evaporated under reduced pressure (10−2 torr). The resulting material consisted of a brown colored paste, which was washed with pentane (3×100 ml). After drying the residue under reduced pressure (10−2 torr) a yellow solid of complex (2) was obtained in 99% yield. 1H NMR (CDCl3) 0.60 (m, 2H, 3J=7.0, CH2—CH2—Si), 0.96 (tr, 3H, 3J=7.4, —CH2—CH2—CH3), 1.22 (tr, 9H, 3J=7.0, CH3—CH2—O), 1.38 (six, 2H, 3J=7.4, —CH2—CH2—CH3), 1.68 (m, 2H, Si—CH2—CH2—), 1.76 (m, 2H, —CH2—CH2—CH3), 3.65 (m, 4H, Si—CH2—CH2—CH2—N and —N—CH2—CH2—N—Bu), 3.82 (qr, 6H, CH3—CH2—O), 4.04 (m, 4H, —N—CH2—CH2—CH2—CH3 and —N—CH2—CH2—N—Bu), 10.01 (s, 1H, N—CH—N) ppm; 13C NMR (CDCl3) 7.32 (1C, Si—CH2—CH2—), 13.58 (1C, —CH2—CH2—CH3), 18.33 (3C, CH3—CH2—O—), 19.63 (1C, —CH2—CH2—CH3), 21.27 (1C, Si—CH2—CH2—), 29.36 (1C, —CH2—CH2—CH3), 48.01, 48.21, 48.51, 50.37 (4C, —CH2—N—CH2—CH2—N—CH2—), 58.53 (3C, CH3—CH2—O—), 158.87 (1C, N—CH—N) ppm; MS/ES+ (m/e) 331 [M+], Anal. Calcd for C16H35N2ClO3Si: C, 52.37; H, 9.61; N, 7.63; Cl, 9.66; Si, 7.65. Found: C, 51.64; H, 9.94; N, 7.60; Cl, 13.61; Si, 7.65.
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH:5]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3].CN(C)C(=N)N(C)C.[CH:38]([C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[CH:42]=[CH:43][NH:44]2)=O>ClCCl>[CH2:9]([O:8][C:6](=[O:7])/[C:5](/[O:4][CH2:2][CH3:3])=[CH:38]/[C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[CH:42]=[CH:43][NH:44]2)[CH3:10]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1cccc2[nH]ccc12)OCC
Reaction time: 16 h
Yield: 107.2 %

Procedure:
To a solution of 35.01 g (81.6 mmol) of (1,2-diethoxy-2-oxoethyl)triphenyl phosphonium chloride in 200 ml of dichloromethane was added at 0° C. 11.01 ml (87.1 mmol) of tetramethyl guanidine and the mixture was warmed to 22° C. The mixture was treated with 7.9 g (54.4 mmol) of 4-formyl-indole and stirring was continued at 40° C. for 16 h. The mixture was treated again with 10.0 g (23.3 mmol) of the Wittig salt and 8.0 ml (24.0 mmol) of tetramethyl guanidine and stirring was continued at 40° C. for 24 h after which time the conversion was complete. The reaction mixture was poured into crashed ice and then extracted twice with MeCl2. The organic layer was washed with water, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica (n-heptane/AcOEt, 95:5 to 4:1) to give 15.12 g of the title compound as a light yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:30]
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1ccccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2ccccc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine.2HCl (70 mg, 0.206 mmol), (2-fluorophenyl)acetic acid (31.8 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The white solid was filtered to give the product. LC/MS (ES) m/z=403.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.25-3.32 (m, 2H), 3.91-3.99 (m, 5H), 4.31 (t, J=8.46 Hz, 2H), 7.16-7.24 (m, 2H), 7.32-7.39 (m, 2H), 7.44 (d, J=8.08 Hz, 1H), 7.53 (s, 1H), 8.15 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[N:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([OH:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=4)[C:13]=3[N:14]=2)[CH:5]=[N:4]1)[CH3:2].[OH2:28].[C:29]1([CH3:39])C=CC(S(O)(=O)=O)=CC=1.O>C(O)CO>[CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[N:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([CH3:26])([O:27][CH2:39][CH2:29][OH:28])[CH3:25])=[CH:20][CH:19]=4)[C:13]=3[N:14]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)O)cc4)c3n2)cn1
Reactant: O
Solvent: OCCO
Product: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)OCCO)cc4)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 2-{4-[5-(1-ethyl-1H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-phenyl}-propan-2-ol (138 mg, 0.38 mmol) in ethane-1,2-diol (1 ml) is added toluene-4-sulfonic acid monohydrate (89 mg, 0.42 mmol). The reaction mixture is stirred for 16 hours at ambient temperature. The mixture is then heated to 80° C. and the resulting clear solution is stirred at this temperature for 1 hours. The reaction mixture is cooled to room temperature and water is added. The resulting precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent to afford 2-(1-{4-[5-(1-ethyl-1H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-phenyl}-1-methyl-ethoxy)-ethanol (“A127”) as yellow powder; HPLC/MS1.67 min (A), [M+H] 409;
Reaction SMILES: C(N(CC)CC)C.[I:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23]>ClCCl>[I:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](=[O:14])[NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1ccc(I)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Triethylamine (5.4 ml) was added to a solution of 4-iodobenzoyl chloride (5.06 g) in dichloromethane (30 ml) at 5° C. Glycine methyl ester hydrochloride (2.4 g) was then added to the reaction mixture and the mixture was stirred at 5° C. for 2 hours. The mixture was then stirred at ambient temperature overnight. Dichloromethane (100 ml) was added and the mixture was washed with water (2×100 ml), dried (MgSO4) and evaported. The residue was triturated with pentane to give a solid which was collected by filtration to give methyl 4-iodohippurate, m.p. 166-168° C. NMR: 3.65(3H,s), 4.0(2H,d), 7.65(2H,m), 7.88(2H,m) and 9.0(1H,m); m/z 320(M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:12]1[NH:13][C:14]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:16]=1)([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:16]=[C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][NH2:7])[NH:13][C:14]=2[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[CH:18][C:19]=1[O:24][CH3:25]
Reactant: COc1cc(-c2nc(C(C)(C)CNC(=O)OC(C)(C)C)[nH]c2-c2ccncc2)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nc(C(C)(C)CN)[nH]c2-c2ccncc2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
A solution of Example 1 (112 mg, 0.245 mmol) in dichloromethane (2 ml) containing trifluoroacetic acid (1 ml) was stirred at room temperature for 3 hours. The solution was concentrated at reduced pressure and the residue was partitioned between saturated sodium hydrogen carbonate solution and ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure to give the title compound (59 mg, 68%) as a solid; MS(ES+) m/e 357/359 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Reactant: CCOC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CNCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (20 mg), ethyl glycinate (10 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (21 mg). The reaction was stirred at 20° C. for 1 h. The reaction mixture was partitioned between DCM (25 mL) and water (25 mL). The organic phase was evaporated to give ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}glycinate (D89) as a brown oil (20 mg), which was used directly in the next hydrolysis step. MS (ES): C26H29ClN4O4 requires 496; found 497.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)=[N+]=[N-].[OH2:19]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)[O:19][CH:12]1[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: O
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C(OC1C=CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of (3-chloro-4-methanesulfonyl-phenyl)-diazo-acetic acid methyl ester (Example 6; 489 mg, 1.69 mmol) in dichloromethane (10 mL) at 25° C. was treated with 2-cyclohexen-1I-ol (0.42 mL, 4.23 mmol) followed by rhodium (11) acetate dimer (15 mg, 0.034 mmol) and the resulting solution was stirred at 25° C. for 1 h. The reaction mixture was diluted with dichloromethane (10 mL), then was poured into water (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 40S column, 75/25 hexanes/ethyl acetate) provided rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid methyl ester (350 mg, 58% yield) as a colorless oil: EI-HRMS m/e calcd for C16H19ClS O5 (M+) 358.0642, found 358.0640.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:14](Br)[C:15]#[CH:16]>C1COCC1>[CH2:16]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCn1ccc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.65 g (50% in mineral oil, 13.5 mmol) NaH are batchwise added to a solution, cooled to 0° C., of 2.0 g (13.5 mmol) 1H-indole-5-carbaldehyde in 80 mL THF and after heating to RT stirred for 15 min. Then a solution of 1.6 mL (80% in toluene, 15 mmol) propargyl bromide in 20 mL THF is slowly added dropwise and the reaction mixture is stirred overnight at RT. The mixture is evaporated down i. vac., the residue is combined with water, the aqueous phase is exhaustively extracted with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient: cyc/EtOAc 4:1 to 2:1).