Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:18][C:19](C)([O-])[CH3:20].[K+].C(Br)C=C>C(O)(C)(C)C>[CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:20][CH:19]=[CH2:18]
Reactant: COC(C(=O)c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C=CCBr
Product: C=CCc1ccccc1C(=O)C(OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Benzoin methyl ether (50 g) and t-butanol (500 g) were added to a 1 liter, 3neck, round bottom flask equipped with magnetic stirrer, and placed in an oil bath at 80° C. To this mixture, 33.7 g of potassium t-butoxide was added and the solution stirred for 15 minutes. Allyl Bromide (42.3 g) was added dropwise over a 1 hour period and stirring was continued at 85° C. for 2 more hours then cooled to room temperature. After evaporation of t-butanol and filtration of potassium bromide, the product was distilled at 125° C.±2° C. and 0.05 mgHg to yield 49.2 g of allylbenzoin methyl ether which crystallized upon cooling.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:10][C:11]1[CH:16]=[C:15]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)[CH:14]=[CH:13][N:12]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1oc(Br)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1oc(-c2ccnc(Cl)c2)cc1C=O
Reaction time: 8 h
Yield: 53.9 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 2-chloropyridine-4-boronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.2 g, 55%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoate (14) in 30% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of the tert-butyl group (4 hours). The reaction was diluted with DCM and concentrated with a stream of nitrogen. The residue was then diluted in MTBE and washed once with 1M citric acid (adjusted to pH3). The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo to afford (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoic acid (15) as a waxy solid that was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH3:2]>CO.CCOC(C)=O.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN(Cc1ccc(/C=C/c2ccccc2)cc1)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(Cc1ccc(CCc2ccccc2)cc1)S(C)(=O)=O
Reaction time: 20 h
Yield: 99.5 %

Procedure:
A solution of trans-7-[methanesulfonyl-(4-styryl-benzyl)-amino]-heptanoic acid ethyl ester (0.60 g) in MeOH (5 mL) and EtOAc (50 mL) was added to 10% Pd/carbon (0.2 g). The reaction mixture was placed on a Parr hydrogenator and was hydrogenated for 20 h at 50 psi. The reaction mixture was filtered through celite and concentrated in vacuo to afford 7-[methanesulfonyl-(4-phenethyl-benzyl)-amino]-heptanoic Acid ethyl ester (0.60 g). 1H NMR (400 MHz, CDCl3) δ 7.30-7.10 (m, 9H), 4.32 (s, 2H), 4.10 (q, 2H), 3.12 (t, 2H), 2.90 (s, 4H), 2.79 (s, 3H), 2.25 (t, 2H), 1.60-1.45 (m, 4H), 1.30-1.19 (m, 7H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)CCC>CN(C)C=O.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>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:28]2[O:29][CH:30]=[CH:31][CH:32]=2)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2ccco2)c2nc(-c3ccccc3)sc2c1O
Temperature: 130 °C
Reaction time: 0.42 h
Yield: 57.9 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (248 mg, 0.66 mmole), 2-(tributylstannyl)furan (414 μl, 1.31 mmole) and bis(triphenylphosphine)-palladium(II) dichloride (46 mg, 0.06 mmole) in dimethylformamide (2.5 ml) was stirred at 130° C. for 25 min before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (140 mg). MS: (+) m/z 367.00 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:36]3[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][CH:37]=3)(=[O:41])=[O:40])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(Cl)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-chlorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.84-7.79 (2H, m), 7.48-7.21 (11H, m), 6.24 (1H, br.s), 3.48-3.42 (2H, m), 2.83 (2H, t, J=7.1 Hz), 2.32 (3H, s), 2.24 (3H, s).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH3:15]I>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[C:10]([CH3:15])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:14]
Reactant: CI
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Product: CCN(CC)C(=O)c1c(C)cccc1Cl
Yield: 92 %

Procedure:
The compound from example e (1.0 eq) and MeI (3.0 eq) were combined according to Method A. The crude product was purified by HPLC with 1:4 EtOAc/hexanes to give 5.2 g of N,N-diethyl 2-chloro-6-methylbenzamide as a yellow solid, a 92% yield. m.p. 48°-49° C.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]([N:16]1[C:28]2[CH:27]=[C:26]([C:29]([OH:31])=O)[CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:15])[CH3:14].C(=O)(O)O.[NH2:36][C:37]([NH2:39])=[NH:38]>CN(C=O)C>[NH2:38][C:37]([NH2:39])=[N:36][C:29]([C:26]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH:13]([CH3:15])[CH3:14])[C:28]=2[CH:27]=1)=[O:31]
Reactant: CC(C)n1c2ccccc2c2ccc(C(=O)O)cc21
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)n1c2ccccc2c2ccc(C(=O)N=C(N)N)cc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A 134 mg portion of CDI was added to 4 ml DMF solution of 140 mg 9-isopropyl-9H-carbazole-2-carboxylic acid, followed by stirring at 50° C. for 1 hour. After spontaneous cooling to room temperature, 238 mg of guanidine carbonate was added thereto, followed by stirring overnight at room temperature. After evaporation of the solvent, water was added thereto and the thus precipitated solid was purified by a silica gel column chromatography (Chromatorex (registered trademark), methanol/chloroform) to obtain 157 mg of N-(diaminomethylene)-9-isopropyl-9H-carbazole-2-carboxamide as a pale yellow solid.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([Cl:13])[CH:6]=1)C=C.[CH2:14]([C:17]1C(O)=CC(Cl)=C(C=1)C#N)[CH:15]=C>>[CH2:17]([C:6]1[C:7]([Cl:13])=[C:8]([CH:11]=[CH:12][C:5]=1[OH:4])[C:9]#[N:10])[CH:14]=[CH2:15]
Reactant: C=CCc1cc(C#N)c(Cl)cc1O
Reactant: C=CCOc1ccc(C#N)c(Cl)c1
Product: C=CCc1c(O)ccc(C#N)c1Cl
Yield: 51 %

Procedure:
Following the process described in example 6 (point B), starting from 4-allyloxy-2-chlorobenzonitrile, a mixture of 5-allyl-2-chloro-4-hydroxybenzonitrile and 3-allyl-2-chloro-4-hydroxybenzonitrile was obtained. The two isomers were separated by chromatography through a silica gel column. Eluting with petroleum ether:ethyl ether, 8:2, the isomer 5-allyl-2-chloro-4-hydroxybenzonitrile (39% yield) was recovered and eluting with petroleum ether:ethyl ether, 6:4, the isomer 3-allyl-2-chloro-4-hydroxybenzonitrile was recovered (51% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](O)(=[O:13])[CH3:12]>S(=O)(=O)(O)O.O>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 80 °C

Procedure:
6 Grams of 4-hydroxybenzoic acid and 8.2 g of anhydrous acetic acid were placed in a two-necked flask and mixed. While the mixture was cooled with water, 5 drops of sulfuric acid was added. After termination of heat generation, the mixture was heated at 80° C. for 30 minutes. Then, the reaction mixture was poured into cold water, and a precipitated crystal was filtered.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:17][CH:18]([CH2:21][CH3:22])[CH2:19][NH2:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH3:6][CH:4]([CH3:5])[CH2:3][C@H:2]([NH:1][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([NH:20][CH2:19][CH:18]([CH3:17])[CH2:21][CH3:22])=[O:9]
Reactant: CCC(C)CN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCC(C)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of Boc-Leu-OH (61.3 mg, 0.26 mmol), 2-methylbutylamine (0.046 ml, 0.40 mmol) and 3 ml of MeCN in a round bottom flask equipped with a magnetic stirring bar was added DIEA (0.092 ml, 0.53 mmol) followed by HBTU (120 mg, 0.32 mmol). The reaction mixture was stirred at room temperature for 16 hours at which point TLC analysis showed that the reaction was complete. The mixture was concentrated under reduced pressure. 10 ml of DCM was added and this mixture was washed with water (×3), citric acid (1M, ×3), and brine (×1), dried over Na2SO4 and concentrated under reduced pressure. The crude 1H NMR showed that the product was pure enough to carry over to the next step. 1H NMR (CDCl3, 300 MHz): δ 6.75 (b, 1H), 5.21 (b, 1H), 4.18 (b, 1H), 3.17 (m, 2H), 1.77-1.07 (m, 16H), 0.98 (m, 12H) ppm; 13C NMR (CDCl3, 75 MHz): δ 172.9, 156.0, 53.3, 45.1, 41.4, 35.0, 28.4, 27.1, 27.1, 27.0, 24.9, 23.0, 22.3, 17.2, 17.1, 11.4, 11.3 ppm. HRMS (ESI+) [M+H]+ calcd. for C16H33N2O3 301.2485, found 301.2489.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].P(OCC)(OCC)([S-])=[S:19]>O>[C:1]([C:3]1[C:4]([CH:14]2[CH2:15][CH2:16][CH2:17]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:19])[NH2:2]
Reactant: CCOP(=S)([S-])OCC
Reactant: COC(=O)c1cc(C#N)c(C2CCC2)cc1C
Solvent: O
Product: COC(=O)c1cc(C(N)=S)c(C2CCC2)cc1C
Temperature: 80 °C
Yield: 78 %

Procedure:
To a round-bottom flask was added methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (compound 6.4, 3.63 g, 0.015 mol), O,O′-diethyl dithiophosphate (10 mL) and water (1 mL). The reaction mixture was heated to 80° C. for 3 hours (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed successively with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (hexanes/ethyl acetate=80/20 to 50/50) to yield the title compound as a yellow solid (3.06 g, 78% yield). m/z (ES+) 264 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 7.93 (s, 1H), 7.82 (s, 1H), 7.26 (s, 1H), 6.92 (s, 1H), 4.19 (m, 1H), 3.89 (s, 3H), 2.64 (s, 3H), 2.40 (m, 2H), 2.29-2.15 (m, 2H), 2.12-2.00 (m, 1H), 1.95-1.84 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16]([C:27]4[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([N+:34]([O-])=O)[CH:28]=4)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]>[Pd].CO.C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16]([C:27]4[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=4)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)c([N+](=O)[O-])c4)nc(N4CCOCC4)c3s2)CC1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)c(N)c4)nc(N4CCOCC4)c3s2)CC1
Yield: 52.4 %

Procedure:
4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-2-nitro-phenylamine (200 mg) was stirred under hydrogen balloon with palladium on carbon (10%, 70 mg) in a mixture of MeOH and DCM (1:1, 10 ml) at room temperature overnight. The reaction mixture was then filtered through Celite®, volatiles removed in vacuo, and the residue purified by flash chromatography to give 4-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-benzene-1,2-diamine (99 mg).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[OH:21])[C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH2:10]>N1C=CC=CC=1>[C:1]([O:21][C:20]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CCc1cc(C(=O)OC)ccc1OC(C)=O
Reaction time: 14 h
Yield: 87.7 %

Procedure:
Acetic anhydride (200 μL, 218 mg, 2.13 mmol) was added dropwise to a solution of phenol 5 (315 mg, 1.64 mmol) in pyridine (1.5 mL) at room temperature. The mixture was stirred for 14 hours before the solvent was removed. The residue was purified by chromatography (10:1, hexanes:EtOAc) to afford 6 (337 mg, 88%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.95-7.90 (m, 2H), 7.11 (d, J=8.2 Hz, 1H), 5.92-5.83 (m, 1H), 5.12-5.03 (m, 2H), 3.88 (s, 3H), 3.33 (d, J=6.5 Hz, 2H), 2.29 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 169.2, 166.8, 153.0, 135.6, 132.7, 132.4, 129.4, 128.4, 123.0, 117.2, 52.6, 35.0, 21.3; IR (neat) νmax 3080, 3005, 2980, 2953, 2916, 2845, 1765, 1722, 1639, 1609, 1589, 1493, 1437, 1418, 1369, 1285, 1263, 1190, 1163, 1121 cm−1; HRMS (ESI+) m/z 235.1076 (M+H+, C13H15O4 requires m/z 235.0970).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][CH2:11]Cl.[H-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cccnc1Br
Temperature: -20 °C

Procedure:
50 g of 2-bromo-3-hydroxypyridine was suspended in 200 ml of tetrahydrofuran, to which 33 ml of chloromethyl methyl ether was added. The mixture was cooled to −20° C. and 17 g of 60% oily sodium hydride was portionwise added while stirring. After the addition of sodium hydride, the refrigerant was removed and the mixture was stirred at room temperature for 3.5 hours. In an ice bath, ice water was portionwise added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (10–15% ethyl acetate/hexane), to give 35 g of the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.[Cl:22][CH2:23][CH2:24][CH2:25]I>C1COCC1>[Cl:22][CH2:23][CH2:24][CH2:25][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[C:19]([OH:21])=[O:20]
Reactant: ClCCCI
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
Step AC (1): NaHMDS (1.0 M in THF, 100 mL, 100 mmol) was added to a stirred solution of 2-(4-fluorophenyl)acetic acid (7.71 g, 50.0 mmol) in THF (100 mL) at 0° C. The resulting mixture was aged for 20 min at 0° C. and neat 1-chloro-3-iodopropane (5.27 mL, 50.0 mmol) was added. The mixture was allowed to warm to rt. After 16 hr, the reaction was quenched with water (3 mL). The crude mixture was concentrated in vacuo. Aqueous NaOH (1 M, 150 mL) was added to the residue and the resulting mixture was extracted with Et2O (2×100 mL). The basic layer was acidified with aqueous HCl (1 M, 200 mL) and the resulting solution was extracted with Et2O (2×100 mL). The combined organic layers from the acidic extraction were washed with mixture of brine/1N HCl/sodium sulfite, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified using silica gel column chromatography (0-10% EtOAc/hexane, linear gradient). The pure fractions were combined and concentrated to afford 5-chloro-2-(4-fluorophenyl)pentanoic acid (7.59 g, 29.6 mmol, 59% yield) as a light brown solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.30 (dd, J=8.55, 5.19 Hz, 2 H) 7.04 (t, J=8.70 Hz, 2 H) 3.58 (t, J=7.78 Hz, 1 H) 3.53 (t, J=5.80 Hz, 2 H) 2.21 (dddd, J=13.35, 10.45, 7.78, 5.34 Hz, 1 H) 1.90-2.01 (m, 1 H) 1.65-1.84 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14]O)=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][Br:37])=[CH:8][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)COc1ccc(CCCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of [4-(3-Hydroxy-propyl)-phenoxy]-acetic acid methyl ester (2.45 g, 10.9 mmol) in DCM (60 mL) is added polymer-supported triphenylphosphine (7.26 g, 21.8 mmol) and carbon tetrabromide (3.47 g, 11.99 mmol) and the resulting reaction mixture is stirred at RT for 15 h. The reaction mixture is filtered to remove the polymer-supported reagent, and then concentrated in vacuo. The residue is purified by chromatography (SiO2, EtOAc:iso-hexane, 1:5) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 7.14 (2H, d), 6.86 (2H, d), 4.69 (2H, s), 3.83 (3H, s), 3.40 (2H, t), 2.74 (2H, t), 2.15 (2H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[NH:25][C:26]2[C:27]3[C:34]([CH3:35])=[C:33]([C:36]([NH2:38])=[O:37])[S:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:9]1)=O)(C)(C)C.Cl>ClCCl.O1CCOCC1>[CH3:35][C:34]1[C:27]2[C:26]([NH:25][C:16]3[CH:17]=[CH:18][C:19]([C:21]([F:22])([F:24])[F:23])=[CH:20][C:15]=3[O:14][C@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[N:31][CH:30]=[N:29][C:28]=2[S:32][C:33]=1[C:36]([NH2:38])=[O:37]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(C(F)(F)F)cc3O[C@H]3CCCNC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[2-((S)-1-tert-butoxycarbonyl-piperidin-3-yloxy)-4-trifluoromethyl-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide (77 mg) was dissolved in dichloromethane (1 ml) and HCl in dioxan (4M; 1.5 ml) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was purfied by chromatography to give the inteded product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH2:11][N:12]=2)=[C:4]([CH3:13])[CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([Br:14])=[CH:11][N:12]=2)=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C1=NCCO1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)ccc1-c1ncc(Br)o1
Temperature: 85 °C
Yield: 13.7 %

Procedure:
2-(4-Bromo-2-methylphenyl)-4,5-dihydro-1,3-oxazole (0.33 g, 1.38 mmol, from Step A) was dissolved in carbon tetrachloride. AIBN (0.003 g) and N-bromosuccinimide (0.18 g, 4.14 mmol) were sequentially added, the mixture was degassed with argon for 5 min and then heated at 85° C. for 24 h. The reaction was filtered, diluted with methylene chloride (200 mL) and washed with saturated sodium bisulfite (2×100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 3% ethyl acetate/hexanes yielded 60 mg of the desired product: 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=8.5 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.16 (s, 1H), 2.67 (s, 3H).