Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[O:17]1C[CH2:20][CH2:19][CH2:18]1>CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[CH3:4]/[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2]\[CH2:1][CH2:20][CH2:19][CH2:18][OH:17]
Reactant: C1CCOC1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCl
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCCCO
Reaction time: 1 h

Procedure:
A solution of 37.5 mL (20.3 mmol, 5.1 eq.) of a 0.54M solution of Grignard reagent (Part B) in tetrahydrofuran and 9 mL of hexamethylphosphoramide at room temperature under argon was treated over 10 minutes with a solution of 955.5 mg (3.97 mmol) of farnesyl chloride (Part A) in 5 mL of tetrahydrofuran. After one hour, the reaction mixture was diluted with a mixture of 1:1 diethyl ether : hexane and quenched with 1M HCl. The organic phase was washed with three 25 mL portions of saturated NaHCO3, three 25 mL portions of H2O, and 25 mL of brine, dried over MgSO4 and evaporated to obtain 995.0 mg of crude product. Purification required two chromatographies. The first was run on 70 g of silica gel, eluting with 1:99 ethyl acetate:CH2Cl2 to provide 484.3 mg of impure material and 307.7 mg of pure title compound. The second chromatography, of the impure fractions, on 50 g of silica gel eluted with 0.75:99.25 ethyl acetate:CH2Cl2 gave 117.2 mg of slightly impure material and 302.8 mg of pure title compound. Combination of pure material from both columns gave a yield a yield of 610.5 mg (58%) of pure desired title isomer.
Reaction SMILES: [H-].[Na+].COP(=O)[O:6][CH3:7].[O:9]=[C:10]([CH:12]([CH3:17])[CH2:13][C:14]#[C:15][CH3:16])[CH3:11].[CH2:18]([CH2:21]OC)[O:19]C>>[O:9]=[C:10]([CH:12]([CH3:17])[CH2:13][C:14]#[C:15][CH3:16])[CH:11]=[CH:15][CH:14]([CH2:13][CH:12]=[CH:10][CH3:11])[CH2:21][C:18]([O:6][CH3:7])=[O:19]
Reactant: CO[PH](=O)OC
Reactant: CC#CCC(C)C(C)=O
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Product: CC#CCC(C)C(=O)C=CC(CC=CC)CC(=O)OC
Reaction time: 1.5 h

Procedure:
To a slurry of 301.6 mg of 50% sodium hydride in mineral oil and 150 ml of anhydrous dimethoxyethane (DME) is added 1.32 g (5.7 mmole) of 2-oxo-3-methylhept-5-yne dimethylphosphonate (prepared as described in U.S. Pat. No. 4,235,93) in 15 ml of DME at 0° C. under an argon atmosphere. The mixture is stirred at 25° for 1.5 hours. To the solution at 25° is added 1.05 g (3.9 mmole) of [1β,2β(5Z),3α,4β]-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (prepared as described in Example 1), in 15 ml of DME. After 1 hour the reaction is quenched with 0.7 ml of glacial acetic acid, concentrated, dissolved in 500 ml of ether, washed with three 100 ml portions of 5% NaHCO3 and 100 ml of brine. The organic layer is dried over MgSO4 and concentrated to give 1.66 g of crude title A compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[NH3:29]>CO.CN(C=O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26]([NH2:29])=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:7]1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12
Reactant: N
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12

Procedure:
Prepared analogously to 1.4 from 0.1 g 4-[2-(trans-4-hydroxy-cyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol (7M) in DMF. Separated from cis isomer by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:4]=1[CH2:5][NH:6][C:7](=[O:15])[CH2:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11].[C:24](C1CC(=O)NC1=O)([O:26][CH2:27][CH:28]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25]>C(Cl)(Cl)Cl.CO.C(O)(=O)C>[NH:11]([C:24]([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:25])[C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][C:7](=[O:15])[NH:6][CH2:5][C:4]1[C:3]([O:2][CH3:1])=[CH:19][C:18]([O:20][CH3:21])=[CH:17][C:16]=1[O:22][CH3:23]
Reactant: O=C1CC(C(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Reactant: COc1cc(OC)c(CNC(=O)CC[C@H](N)C(=O)O)c(OC)c1
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(CNC(=O)CC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(OC)c1

Procedure:
N'(2,4,6-trimethoxybenzyl)-L-glutamine (0.97 g, 3 mmol) was reacted with Fmoc-succinimide as described in Step 3 of Example 1 to give 1.23 g (78%), thin layer chromatography 1 spot Rf 0.35 chloroform/methanol/acetic acid (90:5:5).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH:20]2[CH2:22][CH2:21]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[C:10]([CH:20]2[CH2:21][CH2:22]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2c1c(C1CC1)nn2Cc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c1c(C1CC1)nn2Cc1ccccc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a reaction flask was added 1-benzyl-3-cyclopropyl-4-nitro-1H-indazole (60.0 mg, 0.205 mmol), iron powder (114 mg, 2.05 mmol) and ammonium chloride (10.9 mg, 0.205 mmol). Ethanol (0.8 mL) and water (0.2 mL) were added and the mixture was heated at 85° C. with stirring for 60 minutes. The solvent was removed under reduced pressure. Ethyl acetate (0.8 mL) and triethylamine (0.2 mL) was added and the mixture was heated at 60° C. for 10 minutes. The mixture was filtered through glass fiber filter paper, washing with methanol and ethyl acetate. The filtrate was concentrated under reduced pressure. The material was purified by preparative chromatography, eluting with 3% methanol in dichloromethane, containing 0.5% ammonium hydroxide solution to give 1-benzyl-3-cyclopropyl-1H-indazol-4-amine (36 mg).
Reaction SMILES: O.[C:2]([O-:5])(=[O:4])[CH3:3].[Pb+2:6].[C:7]([O-:10])(=[O:9])[CH3:8]>COC(O)C>[CH3:7][O:4][CH:2]([CH3:3])[O-:5].[Pb+2:6].[CH3:2][O:9][CH:7]([CH3:8])[O-:10]
Reactant: CC(=O)[O-]
Agent: COC(C)O
Agent: [Pb+2]
Solvent: O
Product: COC(C)[O-]

Procedure:
For the multicomponent PZT and PLZT sol-gel thin films to be described in Examples 8 through 14, stock alkoxide solutions were prepared. A lead methoxyethoxide stock solution was prepared by dissolving 37.9 grams of lead acetate hydrate in 300 ml of methoxyethanol at 80° C. The solution was distilled at 110° C. to remove the water and acetate. This lead methoxyethoxide stock solution was analyzed by ICP (inductively coupled plasma) to have a Pb concentration of 87.8 grams/liter (0.422 M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)=[O:24]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccccc1F)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Following the procedure of Example 8, 19.53 g. of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g. of sodium carbonate and 15.8 g. of o-fluorobenzoyl chloride are reacted to give the product as a brown gum.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][NH2:13].[CH:14]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[C:28](OC)[CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]4[N:13]([CH3:12])[C:4](=[O:6])[C:3]5[C:2](=[C:10]([F:11])[CH:9]=[CH:8][CH:7]=5)[N:1]=4)=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(OC2CCN(C3CCCC3)CC2)ccc1C=O
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: CN
Product: Cn1c(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)nc2c(F)cccc2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-3-fluorobenzoic acid, methylamine and 4-[(1-cyclopentylpiperidin-4-yl)oxy]-2-methoxybenzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCN4CCOCC4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K2CO3 (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24 hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil (-7.1 g). Purification on a silica gel column (55 g, SiO2 eluted with MeOH:DCM) yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131°-132° C.
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[CH3:9][C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:12][NH:13][C:14]=1[CH3:15].[CH3:22]C1C(C2C=CC=CC=2)=NNC=1>>[CH2:8]([CH:2]([N:13]1[C:14]([CH3:15])=[C:10]([CH3:9])[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:12]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[CH3:22]
Reactant: Cc1[nH]nc(-c2ccccc2)c1C
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1
Product: CCC(C(=O)N(C)C)n1nc(-c2ccccc2)c(C)c1C

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 4,5-dimethyl-3-phenylpyrazole for 4-methyl-3-phenylpyrazole there was obtained α-ethyl-N,N,4,5-tetramethyl-3-phenylpyrazole-1-acetamide, m.p. 119°-121° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[S:13]1[CH:14]=[CH:15][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Brc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc2c(c1)ccn2-c1ccsc1
Temperature: 180 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
A mixture of indole (5.64 g, 48.3 mmol), 3-bromothiophene (4.84 mL, 51.6 mmol), potassium carbonate (7.16 g, 51.6 mmol), cuprous bromide (298 mg, 2.1 mmol) and N-methylpyrrolidinone (57 mL) is stirred at 180° C. under nitrogen atmosphere for 48 hr. After cooling to room temperature, the reaction mixture is poured into water (300 mL) and then extracted with ethyl acetate. The extract is washed with water, with brine, dried, filtered and concentrated to give a brown oil that is purified by chromatography eluting with heptane-10% dichloromethane. Product containing fraction are combined and concentrated to afford 1-(thien-3-yl)-1H-indole (6.20 g, 64% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:17]3[C:12]([C:13]4[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(O)C.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:17]3[C:12]([C:13]4[CH:29]=[CH:28][C:27]([C:30]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:32])=[CH:26][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2c2ccc(F)cc2)cc1Cl
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)NC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution of (±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 2 (45 mg, 0.10 mmol), methylsulfonamide (12 mg, 0.12 mmol), triethylamine (0.021 mL, 0.15 mmol), and tetrahydrofuran (1.0 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol) followed by 4-dimethylaminopyridine (15 mg, 0.12 mmol) at room temp. The reaction was stirred at room temp overnight. The reaction was concentrated and purified by reverse-phase HPLC (40 to 95% acetonitrile/water/0.05% trifluoroacetic acid) to give the title compound (yellow solid, 20.6 mg, 0.0394 mmol, 39% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70-0.92 (m, 1H), 1.72-1.89 (m, 1H), 2.84-3.04 (m, 2H), 3.35 (s, 3H), 3.98 (ddd, J=13.67, 10.94, 5.08 Hz, 1H), 5.95 (d, J=11.33 Hz, 1H), 6.65-7.58 (m, 6H), 7.67 (d, J=8.98 Hz, 1H), 7.75-7.89 (m, 2H), 8.16 (d, J=8.20 Hz, 1H), 12.17 (s, 1H). ES-MS m/z 523 (M+H).
Reaction SMILES: [NH4+:1].[Cl-:2].C[Al](C)C.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][C:17]#[N:18]>C1(C)C=CC=CC=1>[ClH:2].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][C:17]([NH2:1])=[NH:18]
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COc1ccc(Br)c(CC#N)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1ccc(Br)c(CC(=N)N)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of NH4Cl (3.58 g, 66.37 mmol) in dry toluene (100 mL) was added trimethyl aluminium (2M in toluene, 33.18 mL, 66.37 mmol) at 5° C., then the mixture was warmed to room temperature and stirred for 2 h. A solution of (2-bromo-5-methoxy-phenyl)-acetonitrile (136) (5 g, 22.12 mmol) in toluene (25 mL) was added to the above reaction mixture and the mixture was then stirred for 14 h at 80° C. After completion of the reaction, it was quenched with a suspension of silica gel in chloroform and the reaction mixture was stirred for half an hour at room temperature and filtered through a sintered funnel, the silica gel was washed with methanol and the combined filtrate was concentrated under reduced pressure to get 2-(2-bromo-5-methoxyphenyl)-acetamidine hydrochloride salt as a crude product (137) (4 g, 74.37%) a as white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[O:7])=[N:2]1.Cl[C:29]1[N:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:36][C:35]([F:38])([F:37])[C:32]1[CH:31]=[N:30][C:29]([N:1]2[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C@@H:15]4[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]4)=[CH:11][CH:10]=3)=[O:7])=[N:2]2)=[N:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc[nH]n3)cc2)C1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccn(-c4ncc(C(F)(F)F)cn4)n3)cc2)C1
Reaction time: 20 h
Yield: 23.8 %

Procedure:
(S)-tert-Butyl 2-(4-(1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (33 mg, 0.089 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (16.2 mg, 0.089 mmol) were dissolved in DMSO (0.7 ml) and potassium carbonate (24.5 mg, 0.177 mmol) was added. The reaction mixture was placed on a Büchi shaker for 20 hours at 120° C. After cooling the mixture, water was added followed by extraction with ethyl acetate twice. The combined organic layers were dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (silica gel, 5 g, 25% to 50% EtOAc in heptane) to yield an off-white solid (11 mg, 24%). MS (ISP): 463.1 (100%, [M−tBu+H]+), 519.3 (10%, [M+H]+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3][CH2:2]1.C[O-].[Na+].[CH2:23]([O:25][C:26](=[O:34])[C:27]([S:30]C(=O)C)([CH3:29])[CH3:28])[CH3:24]>C(O)C>[CH2:23]([O:25][C:26](=[O:34])[C:27]([CH3:29])([S:30][CH2:8][CH2:7][CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH3:28])[CH3:24]
Reactant: CCOC(=O)C(C)(C)SC(C)=O
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCOCC2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCCC1CCOCC1
Temperature: 130 °C
Yield: 108.9 %

Procedure:
To a solution of 1.9 g (6.7 mmol) of toluene-4-sulfonic acid 2-(tetrahydro-pyran-4-yl)-ethyl ester in ethanol (20 mL) are added 1.4 g (26.8 mmol) of sodium methoxide, followed by 1.27 g (6.7 mmol) of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester. The reaction mixture is heated in a microwave at 130° C. for 0.5 h. The solvent is removed under reduced pressure. The residue is partitioned between saturated aqueous NaHCO3 solution (25 mL) and DCM (25 mL). The layers are separated and the aqueous phase extracted with DCM (2×25 mL). The combined organic extracts are dried over Na2SO4, filtered and the solvent is removed under reduced pressure to afford 1.9 g of 2-methyl-2-[2-(tetrahydro-pyran-4-yl)-ethylsulfanyl]-propionic acid ethyl ester. Yield: 100%; ES-MS: m/z 261 [M+H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.15-1.38 (5H, m), 1.42-1.70 (12H, m), 2.59-2.71 (1H, m), 3.37 (2H, td, J=11.73, 1.98 Hz), 3.95 (2H, ddd, J=11.04, 3.88, 0.91 Hz), 4.18 (2H, q, J=7.16 Hz)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17].[Cl-].[NH4+]>CCOCC.C(Cl)Cl.CO>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:16](=[O:18])[CH3:17])=[N:3][CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: Cc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc(C)cn1
Temperature: -40 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 2-bromo-5-methylpyridine 49 (1.73 g, 10 mmol) in dry ether (20 ml), cooled to −78° C., was added n-butyllithium (6.25 ml of 1.6M solution in hexanes, 10 mmol, 1 equiv) dropwise. The reaction mixture was allowed to warm to −40° C. for 15 min, then cooled back to −78° C. again. N,N-dimethylacetamide (1.023 ml, 11 mmol, 1.1 equiv) was added dropwise and the mixture was stirred at −78° C. for 2 h. Saturated aqueous ammonium chloride (10 ml) was added and the organic layer was separated. The aqueous layer was extracted with ether (3×10 ml) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give an oily residue that was subjected to flash column chromatography using (5% methanol in methylene chloride) to give compound 51 (0.977 g, 72%) as a yellow oil: TLC Rf=0.48 (silica gel, 25% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.5-8.48 (m, 1H), 7.96-7.93 (d, 3J=8 Hz, 1H), 7.63-7.60 (m, 1H), 2.70 (s, 3H), 2.414 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 200.239, 151.741, 149.704, 137.786, 137.442, 121.663, 26.017, 18.969; HRMS calcd for C8H9NO+Na+ 158.0582; found 158.0580 [M+Na+].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:18]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: Oc1ccccc1
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
4-t-Butylbromobenzene (2.5 mmol), phenol (3.5 or 5.0 mmol), Cs2CO3 (3.5 or 5.0 mmol), (CuOTf)2 PhH (0.0625 mmol, 5.0 mol % Cu), ethyl acetate (0.125 mmol, 5.0 mol %), 1-naphthoic acid (3.5 mmol), molecular sieves (625 mg) and toluene (1.5 mL) were added to an oven-dried test tube which was then sealed with a septum, purged with argon, and heated to 110 C under argon until the aryl halide was consumed as determined by GC analysis. Upon cooling at room temperature, dichloromethane was added and the solvent was removed by filtration. The remaining molecular sieves were stirred with another portion of dichloromethane for 1 h at room temperature, and the solvent was removed by filtration. The combined organic phases were washed with 5% aqueous NaOH. The aqueous layer was then extracted three times with dichloromethane and the combined organic layers were washed with brine. The organic layer was dried over Mg2SO4 and concentrated under vacuum to give the crude product. Purification by flash column chromatography (2% EtOAc/hexane) gave the analytically pure product as a clear oil (457 mg, 81% yield). 1H NMR (300 MHz, CDCl3) δ 7.22-7.34 (m, 4H), 6.90-7.05 (m, 5H), 1.30 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 157.6, 154.7, 146.0, 129.6, 126.5, 122.9, 118.6, 118.5, 34.3, 31.5; IR (neat): 3068, 3962, 8867, 1590, 1508, 1489, 1240 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:18])([C:14]([O:16]C)=[O:15])[C:10](OC)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:19][NH2:20].[CH3:21]O>>[CH3:19][N:20]([CH3:21])[C:10](=[O:11])[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([OH:18])[C:14]([OH:16])=[O:15]
Reactant: CO
Reactant: COC(=O)C(O)(C(=O)OC)c1ccc(Cl)c(Cl)c1
Reactant: CN
Product: CN(C)C(=O)C(O)(C(=O)O)c1ccc(Cl)c(Cl)c1

Procedure:
14.7 g of dimethyl 3,4-dichlorophenylhydroxymalonate were dissolved in 100 ml of methanol, and methylamine was passed in for 1 hour at 60° C. The mixture was evaporated down completely and the crystalline residue was recrystallized from 100 ml of ethanol. 12 g of 3,4-dichlorophenylhydroxymalonic acid dimethylamide (m.p.=158°-60° C.) were obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([O-:12])(=O)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Na+].P(Cl)(Cl)([Cl:16])=O>S1(CCCC1)(=O)=O.C(#N)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([Cl:16])(=[O:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])Cc1cccc(I)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CC#N
Product: O=S(=O)(Cl)Cc1cccc(I)c1
Temperature: 0 °C

Procedure:
A stirred mixture of sodium (3-iodophenyl)methanesulfonate (3.6 g) and phosphoryl chloride (10 ml) in sulpholane (20 ml) and acetonitrile (30 ml) was heated at 70° for 2 h. The mixture was-poured onto crushed ice (200 ml) and the precipitated product was collected and dried to give the title product (2.8 g) LCMS RT=3.47 min.