Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:27])C(=O)C1.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:6][C:7]=1[Cl:27]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Cl)c2)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a stirred solution of tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (2.00 g, CAS-908334-28-1) in DMF (15 ml) was added NCS (1.07 g) and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was then cooled to room temperature and poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, gradient: 0% to 55% EtOAc in hexanes) to afford tert-butyl (RS)-3-(4-amino-3-chlorophenyl)pyrrolidine-1-carboxylate (1.16 g, 51%) as a yellow oil which was used in the next step without further purification. MS (ISP): 299.0 ([{37Cl}M+H]+), 297.2 ([{35Cl}M+H]+), 243.0 ([{37Cl}M+H—C4H8]+), 241.1 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:6][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:30]=1[NH:29][S:26]([C:22]1[C:19]2=[N:20][S:21][N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=1)(=[O:28])=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid as in Example 1, Part C. HPLC: RT=10.36 min. MS (ESI−): mass calcd. for C23H17BrClFN4O5S2, 627.89; m/z found, 625/627 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.46 (s, 1H), 8.37 (dd, J=7.0, 0.8, 1H), 8.22 (dd, J=8.8, 0.9, 1H), 7.75-7.68 (m, 2H), 7.32-7.14 (m, 2H), 7.09-6.88 (m, 3H), 6.53 (d, J=6.8, 1H), 4.98-4.90 (m, 1H), 3.82 (s, 3H), 3.24-3.10 (m, 2H).
Reaction SMILES: [K].[CH:2]([CH:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])=O.[NH2:10][CH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:9][C:8]1[N:10]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)[CH:2]=[C:4]([C:5]#[N:6])[CH:7]=1
Reactant: N#CCC(C#N)C=O
Reactant: NC1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(N)n(C2CCc3ccccc32)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
Formyl succinonitrile potassium salt (36.5 g) and 1-aminoindane (36.6 g) were dissolved in water (100 ml), and acetic acid (100 ml) was added thereto. After agitating the mixture at 100° C. for 30 minutes, the reaction solution was poured into water (1200 ml). The reaction mixture was made basic by adding potassium carbonate and then extracted with ethyl acetate. After the organic layer was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure and the residue (37.4 g) was dissolved in ethanol (450 ml). After potassium ethoxide (35.2 g) was added thereto and the mixture was stirred at room temperature for 30 minutes, the reaction solution was poured into iced water (1500 ml) and extracted with ethyl acetate. After the organic layer was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluting with ethyl acetate-hexane (1:2, v/v) and the fractions were concentrated under reduced pressure to give 2-amino-1-(indan-1-yl)pyrrole-4-carbonitrile (20.4 g, 37%) as oily matter.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=O>C1COCC1>[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccco1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC=Cc1ccco1
Yield: 60.5 %

Procedure:
This compound was synthesized from 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) and 2-furaldehyde (1.92 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (2.69 g, 61%) as a pale yellow oil (bp 136-139° C./0.05 torr). IR: 3500-2500, 1730, 710 cm-1 ; 1H-NMR: 1.40 (m, 8H), 2.35 (m, 4H), 5.55 (m, 1H), 6.30 (m, 3H), 7.35 (s, 1H), 11.40 (bs, 1H). Anal. Calcd. for C13H18O3 : C, 70.25, H. 8.16%; Found: C, 69.98, H, 8.26%. Z:E=79:21.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[S:5]1(=[O:17])(=[O:16])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7][CH:6]1[C:13]([OH:15])=[O:14]>CN(C=O)C>[CH3:3][C:6]1([C:13]([OH:15])=[O:14])[S:5](=[O:17])(=[O:16])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7]1
Reactant: O=C(O)C1Cc2ccsc2S1(=O)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C(=O)O)Cc2ccsc2S1(=O)=O
Temperature: 0 °C

Procedure:
A suspension of sodium hydride (12.3 g, 60% dispersion in oil) in DMF (200 mL, distilled from calcium hydride) was cooled with stirring to 0° C. under a nitrogen atmosphere. Methyl iodide (18.5 mL, 0.29 mol) was added followed by the dropwise addition of 2,3-dihydrothieno[2,3-b]thiophene-2-carboxylic acid-1,1-dioxide (21.33 g. 0.0978 mol) in DMF (200 mL) over a period 1.25 hours. The reaction was stirred at 0° C. for an additional 2.25 hours, then quenched with water (100 mL) and 40% sodium hydroxide (2 mL). The basic solution was stirred for an additional 1 hour at 0° C., until hydrolysis of the ester was complete by tlc. 10% HCl was added to adjust the pH to 6, and the DMF removed in vacuo. The residue was partitioned between ethyl acetate and water. The pH of the aqueous phase was adjusted to 0 with 10% HCl, and the cloudy solution extracted with ethyl acetate (3×500 mL). The volume of ethyl acetate was reduced to 500 mL and extracted with 10% sodium hydroxide (3×300 mL). The aqueous phase was made acidic with concentrated HCl and extracted with two 400 mL portions of ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was removed in vacuo to give an oil which solidified. The solid was triturated with cold methylene chloride (50 mL), filtered and dried in vacuo (0.5 mm, 40° C.) to give the title compound as a light tan powder.
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Cl[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(OCC)C>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Pyridine (40 mL, 492 mmol) was added in a single portion to a chilled solution (0° C.) solution of indole (48 g, 410 mmol) in diethyl ether (820 mL). Ethyl chlorooxoacetate (50 mL, 451 mmol) was added dropwise. The resulting suspension was allowed to warm to ambient temperature over a period of 20 hours. The solid was isolated by filtration and washed with diethyl ether. The solid was combined with water (1 L), stirred for 1 hour, and then isolated by filtration to provide 75 g of ethyl (1H-indol-3-yl)(oxo)acetate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5].CCN(C(C)C)C(C)C.[CH2:27](Cl)[O:28][CH3:29]>C(Cl)Cl>[CH3:27][O:28][CH2:29][O:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5]
Reactant: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(OC2CCCCO2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.1 %

Procedure:
To a solution of 2-hydroxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (10.4 g, 44.0 mmol) in DCM (100 mL) at 0° C. was added DIPEA (11.5 mL, 66.0 mmol) followed by MOMCl (5.0 mL, 66.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography (hexane:EtOAc 70:30) to give 2-methoxymethoxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (10.0 g, 81%). 1H NMR (400 MHz, CDCl3): δ 10.52 (s, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 5.51 (t, J=3.2 Hz, 1H), 5.25 (q, J=6.8 Hz, 2H), 3.87-3.81 (m, 1H), 3.65-3.61 (m, 1H), 3.51 (s, 3H), 2.57 (s, 3H), 2.04-1.58 (m, 6H). MS (ESI) m/z=281 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH2:12]([N:16]=[C:17]=[O:18])[CH:13]([CH3:15])[CH3:14].C(OCC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:17]([NH:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:18])=[O:6]
Reactant: CC(C)CN=C=O
Reactant: NNC(=O)c1cccc(Br)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CNC(=O)NNC(=O)c1cccc(Br)c1
Reaction time: 8 h

Procedure:
5.00 g (23.3 mmol) of 3-bromobenzoic acid hydrazide are placed in 50 ml tetrahydrofuran at room temperature. 2.70 g (27.2 mmol) of isobutyl isocyanate, dissolved in 10 ml tetrahydrofuran, are rapidly added dropwise with stirring to this suspension. The mixture is firstly further stirred at room temperature and then allowed to stand overnight. The precipitate formed after addition of 100 ml diethyl ether is filtered off and then washed with diethyl ether. An initial quantity of 1.42 g (19% of theory) of the target compound is thus obtained. The mother liquor is concentrated, and the residue again slurried in diethyl ether and filtered. After washing with diethyl ether and drying in vacuo, a further 5.62 g (77% of theory) of the target compound remain.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[H-].[Na+].F[C:21]1[C:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:25][CH:24]=[CH:23][N:22]=1>CN1CCCC1=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:21]2[C:26]([CH:27]3[CH2:28][CH2:29][N:30]([C:33](=[O:35])[CH3:34])[CH2:31][CH2:32]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: CC(=O)N1CCC(c2cccnc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
To 4-(benzo[d]thiazol-2-ylamino)phenol (0.327 g, 1.35 mmol) dissolved in N-Methyl-2-pyrrolidinone (3 mL) was added sodium hydride, 60% dispersion in mineral oil (54 mg, 1.4 mmol). After stirring at RT for 10 min, 1-(4-(2-fluoropyridin-3-yl)piperidin-1-yl)ethanone (0.15 g, 0.68 mmol) was added and the reaction mixture was stirred at 140° C. for 16 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (3×) and the combined organics were dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10% to 100% EtOAc in hexane, followed by trituration with Et2O and hexane to provide 1-(4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)piperidin-1-yl)ethanone (0.137 g, 0.308 mmol, 45.7% yield) as off-white solid. MS (ESI, pos. ion) m/z: 445.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10]O.O.C(Cl)(Cl)(Cl)[Cl:14]>>[Cl:14][CH2:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1cccc(CO)c1F
Solvent: O
Product: COc1cccc(CCl)c1F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of (2-fluoro-3-methoxyphenyl)methanol (13 g, 83.2 mmol) in CCl4 (75 mL), PClS (26 g, 128.7 mmol) was added. The resulting mixture was heated at 90° C. for 30 min and then stirred at room temperature for 1 h. The mixture was poured into water (160 mL) and extracted with dichloromethane (2×150 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (1:15 EtOAc/petroleum ether) to give the title compound (11.5 g). 1H NMR (CDCl3): δ 7.10-6.91 (m, 3H), 4.63 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[CH2:13]([N:20]=[C:21]=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([NH:20][C:21]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=NCc1ccccc1
Reactant: COc1cccc2sc(N)nc12
Solvent: C1CCOC1
Product: COc1cccc2sc(NC(=O)NCc3ccccc3)nc12
Temperature: 60 °C

Procedure:
To a stirred solution of 2-amino-4-methoxy-benzothiazole (180 mg, 1 mol) in THF (5 ml) was added benzylisocyanate (166 mg, 1.25 mmol) and the mixture heated to 60° C. for 3 h. After evaporation of the solvent, ether (5 ml) was added and the suspension ultra-sonnicated for 10 min with addition of nHexane (5 ml). This suspension was filtered and washed further with ether/nHexane (1:1) to afford the title compound, after drying under vacuum, as a white solid (220 mg, 70% yield), MS: m/e=313 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.O>C(Cl)Cl>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH2:7][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: c1ccc2cc(Cn3ccnc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of imidazole (15.4 g, 0.226 mol) and 2-bromomethylnaphthalene (22 g, 0.0995 mol) in 200 ml of methylene chloride was stirred at room temperature overnight. The mixture was stirred with 200 ml of water, the organic layer was washed with water (2×200 ml), and stirred with 30 ml of conc. HCl and 200 ml of water. After filtration for the removal of the solid, the methylene chloride layer was discarded, and the aqueous layer was extracted with 200 ml of ether. The above aqueous layer was basified with 3N NaOH solution, extracted with methylene chloride, and the organic layer was dried over magnesium sulfate. The above organic solution was concentrated in vacuo to afford 13.65 g of 1-(2-naphthylmethyl)imidazole, m.p. 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[CH:10]=[N:9]2)[C:5]([NH:18][C:19]([C:21]2([CH3:25])[CH2:24][O:23][CH2:22]2)=[O:20])=[CH:4][N:3]=1.N1CCCCC1.[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:40]#[C:39][C:37]([OH:41])([C:33]4[S:32][CH:36]=[CH:35][N:34]=4)[CH3:38])[CH:15]=3)[CH:10]=[N:9]2)[C:5]([NH:18][C:19]([C:21]2([CH3:25])[CH2:24][O:23][CH2:22]2)=[O:20])=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1nccs1
Reactant: CC1(C(=O)Nc2cnc(N)nc2-n2ncc3ccc(I)cc32)COC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC1(C(=O)Nc2cnc(N)nc2-n2ncc3ccc(C#CC(C)(O)c4nccs4)cc32)COC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of N-[2-amino-4-(6-iodo-1H-indazol-1-yl)pyrimidin-5-yl]-3-methyloxetane-3-carboxamide (76% purity, 20 mg, 0.034 mmol) and piperidine (0.1 mL) was added tetrakis(triphenylphosphine)palladium (7.8 mg, 0.007 mmol), copper(I) iodide (1.2 mg, 0.007 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (I-1) (10.3 mg, 0.068 mmol). The reaction was purged with N2 and stirred at RT for 2 hr. Reaction mixture was concentrated in vacuo. Purification by flash chromatography (Isolute column, 100% DCM to 2% MeOH-DCM) followed by recrystallization (1:1 MeOH-EtOAc mixture) gave the title compound: 1H NMR (500 MHz, MeOD) δ 1.73 (3H, s), 1.98 (3H, s), 4.47 (2H, d, J=5.99 Hz), 5.01 (2H, d, J=6.15 Hz), 7.43 (1H, dd, J=8.28, 1.18 Hz), 7.57 (1H, d, J=3.31 Hz), 7.79 (1H, d, J=3.31 Hz), 7.83 (1H, d, J=8.35 Hz), 8.39 (1H, s), 8.82 (1H, s), 8.92 (1H, s); m/z=+476.1 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:13]([CH3:20])[CH2:14][C:15](OCC)=[O:16]>CC(O)=O>[OH:16][C:15]1[N:1]([C:3]2[CH:8]=[C:7]([CH:6]=[CH:5][N:4]=2)[C:9]([OH:11])=[O:10])[N:2]=[C:13]([CH3:20])[CH:14]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1cc(C(=O)O)ccn1
Solvent: CC(=O)O
Product: Cc1cc(O)n(-c2cc(C(=O)O)ccn2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carboxylic acid (306 mg, 2 mmol, PREPARATION 1) and ethyl 3-oxobutanoate (390 mg, 3 mmol) in AcOH (5 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by prep-HPLC to afford the title compound (72 mg, 16%) as yellow solid. 1H NMR (400 MHz, CD3OD): δ 2.72 (3H, s), 4.86 (1H, s), 7.71 (1H, d, J=4.8 Hz), 8.55 (1H, d J=4.8 Hz), 8.81 (1H, s). [M+H] Calc'd for C10H9N3O3, 220. Found, 220.
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17].C([Li])CCC.[CH2:23]([Si:26](OC)([O:29][CH3:30])[O:27][CH3:28])[CH2:24][CH3:25]>C(O)C>[CH3:17][O:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[Si:26]([CH2:23][CH2:24][CH3:25])([O:29][CH3:30])[O:27][CH3:28]
Reactant: CCC[Si](OC)(OC)OC
Reactant: COc1ccc(Br)c(OC)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCO
Product: CCC[Si](OC)(OC)c1ccc(OC)cc1OC
Temperature: 0 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A 500 mL round bottomed flask was charged with hexane (200 mL, Aldrich) and bromo-2,4-dimethoxybenzene (12.2 g, 56.0 mmol, Aldrich). The contents were cooled to 0° C. and n-butyl lithium (34.7 mL of a 1.6M solution in hexanes, 55.5 mmol, Aldrich) was added over 15 minutes (white precipitate). The contents were stirred at room temperature for ninety (90) minutes. The solution was added, via cannula, into a 1000 mL round bottomed flask containing hexane (300 mL, Aldrich) and propyl-trimethoxysilane (9.8 mL, 56 mmol). The reaction was stirred at room temperature overnight (18 hours). Ethanol (10 mL, Aldrich) was added to quench residual base. The contents were poured into 0.2N HCl (250 mL). The layers were separated and the product extracted into ether (2×150 mL). The combined organic portions were dried (MgSO4), filtered, and the solvent removed via rotary evaporation (16.2 g crude). Distillation under reduced pressure (b.p. 115° C., 0.04 mm Hg) provided 2,4-dimethoxyphenyl-propyl-dimethoxysilane (9.13 g, 33.8 mmol, 61% yield); C13H22O4Si (Mw=270.40); 1H NMR (CDCl3) δ 7.5 (d, 1H), 6.5 (m, 1H), 6.4 (d, 1H), 3.8 (s, 3H), 3.8 (s, 3H), 3.5 (s, 6H), 1.4 (m, 2H), 0.9 (t, 3H), 0.8 (t, 2H); 13C NMR (CDCl3) δ 165.8, 163.2, 137.6, 112.7, 104.6, 97.5, 55.0, 54.9, 50.4, 17.7, 16.2, 15.4; IR (capillary film) ν 2950, 2836, 1596, 1571, 1460, 1299, 1206, 1154, 1089, 1036; MS m/z (relative abundance) 270 (11.1), 227 (45.6), 197 (100), 167 (24.4), 137 (10.9), 121 (22.6), 91 (9.9), 59 (18.4).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:18]([O:17][C:15]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCCN[C@H]1c1ccccc1)OCc1ccccc1
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a solution of (2S,3S)-(−)-3-amino-2-phenylpiperidine (152 mg, 0.86 mmole) (L-tartaric acid salt, [a]D=−57.1 (EtOH, c=0.1138)) in methylene chloride (10 mL) at room temperature was added benzyl chloroformate (0.123 mL, 0.86 mmole) and diisopropylethylamine (0.45 mL, 2.58 mmole). The reaction was stirred for 16 hours and was then diluted with methylene chloride and quenched by addition of water. The mixture was separated and the aqueous was reextracted with 2 additional aliquots of methylene chloride. The organic layers were successively washed with a portion of brine, dried over sodium sulfate, combined and evaporated. The residue was purified by flash chromatography (5% methanol in methylene chloride) to afford 214 mg (80%) of the title compound. NMR (CDCl3): δ 1.55 (br. d, J=9 Hz, 1H), 1.6-1.9 (m, 2H), 2.02 (br. d, J=9 Hz, 1H), 2.79 (dd, J=9 and 10 Hz, 1H), 3.22 (dd, J=1 and 10 Hz, 1H), 3.91 (br. s, 1H), 4.01 (dd, J=1 and 8 Hz, 1H), 4.89 (s, 2H), 5.65 and 5.88 (2br. s, 1H), 7.1-7.4 (m, 10H).
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](Cl)=[O:16].[NH2:18][C:19]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:39]([S:36]([C:33]1[CH:32]=[CH:31][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:19]([NH:18][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)=[O:16])=[C:20]([CH:25]=2)[C:21]([O:23][CH3:24])=[O:22])=[CH:35][CH:34]=1)(=[O:38])=[O:37])[CH3:40]
Reactant: O=C(Cl)c1ccccn1
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc(N)c(C(=O)OC)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccc(Oc2ccc(NC(=O)c3ccccn3)c(C(=O)OC)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
With cooling with ice, 4.4 ml of triethylamine and 2.8 g of picolinic acid chloride hydrochloride were added to a chloroform (30 ml) solution of 2.65 g of methyl 2-amino-5-[4-(ethylsulfonyl)phenoxy]benzoate, and stirred at room temperature for 90 minutes. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1 to 1/1) to obtain 1.9 g of the entitled compound as a creamy white solid.