Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:37])=[CH:23][CH:22]=2)[C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]3=[O:37])=[CH:23][CH:22]=2)[C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C1CCCC1
Reaction time: 1 h

Procedure:
640 μl (7.4 mmol) of trifluoroacetic acid were added dropwise to a solution of 300 mg (0.740 mmol) of tert-butyl(+)-cyclopentyl{4-[(1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-ethanoate in 1.5 ml dichloromethane. After 1 h of stirring, the reaction mixture was concentrated under reduced pressure and the residue was dried under high vacuum. This gave 267 mg (100% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:23]([C:30]1[N:31]=[C:32]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[O:33][C:34]=1[CH2:35]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([C:30]1[N:31]=[C:32]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[O:33][C:34]=1[CH2:35][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1oc(CC2CCCCC2)nc1Cc1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(Cc2oc(CC3CCCCC3)nc2Cc2ccccc2)CC1
Yield: 81 %

Procedure:
A suspension containing 2-methoxyphenylpiperazine (2.0 mmole), potassium carbonate (4.0 mmole), potassium iodide (1.0 mmole) and 4-benzyl-5-chloromethyl-2-cyclohexylmethyl oxazole (2.0 mmole) from example 8, was stirred in acetone (20 ml) at ambient temperature for 18 hr. The solvent was removed in vacuo, water (50 ml) added and the product extracted into ethyl acetate (3×50 ml). The combined organics were washed with water (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by “flash” chromatography over silica gel to afford the titled compound as an off-white crystalline powder (1.62 mmole, 81% yield). This was transformed into its mono-fumarate salt, an off-white crystalline powder, using the procedure outlined in example 10 above.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([C:23]1[S:24][C:25]([CH2:28][N:29]2[C:33](=[O:34])[CH2:32][NH:31][C:30]2=[O:35])=[CH:26][CH:27]=1)[NH:6][C:7](=[O:22])[CH:8]([CH2:17][S:18]C(=O)C)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.[K+].[Br-]>>[NH:31]1[CH2:32][C:33](=[O:34])[N:29]([CH2:28][C:25]2[S:24][C:23]([CH:5]([C:4]([OH:36])=[O:3])[NH:6][C:7](=[O:22])[CH:8]([CH2:17][SH:18])[CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:27][CH:26]=2)[C:30]1=[O:35]
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(CN2C(=O)CNC2=O)s1
Agent: [Br-]
Agent: [K+]
Product: O=C(NC(C(=O)O)c1ccc(CN2C(=O)CNC2=O)s1)C(CS)CCc1ccccc1

Procedure:
The title compound was prepared from 2-[5-(imidazolidin-2,4-dion-3-ylmethyl)thien-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester (Description 62) by the procedure described in Example 27. vmax (KBr) 3391, 1714 and 1638 cm-1. m/z 479 (MNH4+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][CH:5]=2>C(O)C.[Pd]>[NH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]([CH3:1])=[CH:10]2
Reactant: CCOC(=O)Cn1c(C)cc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cn1c(C)cc2cc(N)ccc21
Reaction time: 4 h
Yield: 96.5 %

Procedure:
A suspension of 2-methyl-5-nitro-1H-indole-1-acetic acid, ethyl ester (6.2 g) in ethanol (600 ml) in the presence of 10% palladium on charcoal (0.6 g) was stirred under a hydrogen atmosphere at 3 bar for 4 hours. The mixture was filtered through celite and the filtrate evaporated to give the sub-title compound as a pink viscous oil (5.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11]=1[CH2:12]O)=[CH:9][CH:8]=[CH:7][CH:6]=2.P(Br)(Br)Br.[CH3:24][NH:25][CH3:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11]=1[CH2:12][N:25]([CH3:26])[CH3:24])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CNC
Reactant: OCc1c(Cl)nc(-c2ccccc2)c2ccccc12
Agent: BrP(Br)Br
Solvent: Cc1ccccc1
Product: CN(C)Cc1c(Cl)nc(-c2ccccc2)c2ccccc12

Procedure:
8.2 g 3-Chloro-4-hydroxymethyl-1-phenyl-isoquinoline are suspended in 300 ml toluene and 16.2 g phosphorus tribromide are added thereto while cooling with ice. After a 10 hours' stirring at room temperature dimethylamine is introduced until an alcaline reaction occurs. The reaction mixture is concentrated and water is added to the residue. Extraction with acetic acid ester gives a yellow oil, that crystallizes slowly. Melting point 75° to 77° C. Hydrochloride: 244° to 246° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][CH2:39][CH3:40]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:38][CH2:39][CH3:40])[CH:24]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: CCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.50 g) and 1-bromopropane (0.1 mL) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 17, 5-hydroxy-N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained. melting point: 161° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5])#[N:2].[C:11]([O:14][C:15](=O)C)(=O)[CH3:12].C(OCC)(OCC)OCC>>[C:1]([C:3](=[CH:15][O:14][CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5])#[N:2]
Reactant: CC(C)COC(=O)CC#N
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C#N)C(=O)OCC(C)C

Procedure:
A mixture of isobutyl cyanoacetate (30 g), acetic anhydride (58 ml) and triethyl orthoformate (43 ml) was heated under reflux for 6 hours. The volatile material was evaporated and the residue was distilled to give isobutyl 2-cyano-3-ethoxy-2-propenoate, b.p. 130°-133° C./0.4 mm. A solution of this (6 g) in ethanol (30 ml) was mixed with benzylmethylamine (4 ml). The mixture was heated under reflux for 10 minutes and then cooled and diluted with water (50 ml). The solid was filtered and recrystallised from ethanol giving isobutyl 3-(benzylmethylamino)-2-cyano-2-propenoate, mp 105°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[N:13]=1.Cl[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1.FC(F)(F)C1C=CC(CN2C(=O)N3N=C(C4C=CC=CC=4Cl)C(C4C=CC(Cl)=CC=4)=CC3=N2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[N:15]([CH2:26][C:27]3[CH:32]=[N:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=3)[N:16]=2)[N:13]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12

Procedure:
The title compound was prepared from 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (79 mg, 0.22 mmol) and 5-(chloromethyl)-2-(trifluoromethyl)pyridine (74 mg, 0.38 mmol) according to the procedures described for 2-(4-(trifluoromethyl)benzyl)-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (Example 2). The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-80%) in hexanes to obtain the desired product as a yellow foam, which was lyophilized in acetonitrile to afford 87 mg (76%) of the title compound as a yellow powder. LC/MS (method A): retention time=3.76 min, (M+H)+=516. 1H NMR (CDCl3, 400 MHz): δ 8.86 (s, 1H), 8.02 (d,J=8.3 Hz, 1H), 7.47 (m, 1H), 7.42 (s, 1H), 7.33 (m, 2H), 7.25 (m, 2H), 7.20 (d,J=8.8 Hz, 2H), 7.02 (d,J=8.8 Hz, 2H), 5.34 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[N:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:21][C:22]2[CH:27]=[N:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[CH:24][CH:23]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
A mixture of ethyl (1-benzyl-3-hydroxy-1H-pyrazol-4-yl)acetate (390 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg), potassium carbonate (414 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (649 mg, yield 80%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12].Br[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12])[CH3:20]
Reactant: Nc1ccc2ccccc2c1N
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNc1c(N)ccc2ccccc12

Procedure:
A solution of VII (11.4 g, 58 mmol) and ethyl 3-bromopropionate (7.5 mL, 58 mmol) in DMF (120 mL) was heated to 50° C. for 8 h. The reaction mixture was poured into water and neutralized with NaHCO3. The products were extracted into CH2Cl2 (2×200 mL). The combined organics were washed with water (4×200 mL) and dried over Na2SO4. The solvent was evaporated in vacuo and the products separated by flash chromatography using 27% EtOAc in hexane as the eluant to give the product VIII, 2.60 g (17%) as a brown solid: MS m/z 259 (MH+); 1H NMR (DMSO-d6) δ 1.22 (t, 3H), 2.64 (t, 2H), 3.09 (br t, 2H), 4.05 (br s, 1H), 4.09 (q, 2H), 5.19 (br s, 2H), 7.04 (d, 1H), 7.13 (dd, 1H), 7.33 (dd, 1H), 7.40 (d, 1H), 7.66 (d, 1H) and 7.97 (d, 1H); and the product XII, 2.06 g (13%) as a brown solid: MS m/z 259 (MH+); H NMR (DMSO-d6) d 1.21 (t, 3H), 2.63 (t, 2H), 3.43 (br m, 2H), 4.10 (q, 2H), 4.65 (br s, 1H), 4.97 (br s, 2H), 7.04 (d, 1H), 7.11-7.18 (m, 2H), 7.27 (dd, 1H), 7.62 (d, 1H), and 7.94 (d, 1H)
Reaction SMILES: [CH2:1]1[CH:5]([OH:6])[CH2:4][NH:3][CH2:2]1.C(N(CC)CC)C.[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:3]2[CH2:2][CH2:1][CH:5]([OH:6])[CH2:4]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH3:17]
Reactant: OC1CCNC1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of DL-3-pyrrolidinol (0.87 g, 10 mmol) in dichloromethane (10 ml) was added triethylamine (1.21 g, 12 mmol) and 4-butoxybezenesulfonyl chloride (2.69 g, 10.5 mmol). The mixture was stirred at room temperature for 2 h. It was then treated with 10 ml of saturated sodium carbonate solution for 18 h. The mixture was diluted with water, and the organic solvents were evaporated. The resulting suspension was filtered, and the precipitate was washed with water and hexanes, and dried to give 2.89 g of an off-white solid; m.p. 83-84° C.; MS (ES) m/z 299.9 (MH+); HRMS (CI) Calcd. for C14H22NO4S (MH+): 300.1269, Found: 300.1272.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH2:12])=[O:11])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC#N>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:2]=1)(=[O:11])[NH2:12]
Reactant: NC(=O)c1n[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1nc(C(N)=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a suspension of 1H-indazole-3-carboxamide [90004-04-9](2.00 g, 12.4 mmol) and potassium carbonate (4.12 g, 29.8 mmol) in CH3CN (60 mL) was added tert-butyl bromoacetate (2.20 mL, 14.9 mmol) dropwise at RT, and the resulting mixture was refluxed for 16 h. The mixture was then cooled to RT and filtered, the solid was washed with CH3CN and the filtrate was concentrated under vacuum. The residual oil was used directly in the next step without further purification. MS (LC/MS): 276.0 [M+H]+; tR (HPLC conditions d): 3.22 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[C:19]([F:18])([F:28])[F:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccccc2C(F)(F)F)=N1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (93.2 mg, 0.40 mmol), 2-trifluoromethyl-benzylbromide (95.6 mg, 0.40 mmol) and K2CO3 (83.01 mg, 0.60 mmol) in acetonitrile (10 mL) was heated to reflux under argon for 1 hr. Cooled to r.t. and the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give a residue which was triturated with EtOAc and filtered to give 4-oxo-2-(2-trifluoromethyl-benzylamino)-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as a white solid (75.0 mg, 48.1%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]4[CH:29]5[CH2:30][C:25]6([C:32]([O:34]C)=[O:33])[CH2:26][CH:27]([CH2:31][CH:23]4[CH2:24]6)[CH2:28]5)=[O:20])[CH2:15]3)=[N:12][CH:13]=2)=[CH:4][C:3]1=[O:36].O.[Li+].[OH-].Cl>CO>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]4[CH:23]5[CH2:24][C:25]6([C:32]([OH:34])=[O:33])[CH2:26][CH:27]([CH2:28][CH:29]4[CH2:30]6)[CH2:31]5)=[O:20])[CH2:15]3)=[N:12][CH:13]=2)=[CH:4][C:3]1=[O:36]
Reactant: COC(=O)C12CC3CC(C1)C(OC(=O)N1CCC(c4ncc(-c5ccn(C)c(=O)c5)cn4)C1)C(C3)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ccc(-c2cnc(C3CCN(C(=O)OC4C5CC6CC4CC(C(=O)O)(C6)C5)C3)nc2)cc1=O
Yield: 57.3 %

Procedure:
To a solution of 1-(methoxycarbonyl)adamantan-4-yl 3-(5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2-yl)pyrrolidine-1-carboxylate (36 mg, 0.073 mmol) in MeOH (6 mL)/water (2 mL) was added LiOH (22 mg, 0.73 mmol). The reaction mixture was heated to reflux for 1 h. The formed mixture was concentrated to give an oil which was adjusted pH=5 by 0.5 M HCl and extracted with EtOAc (10 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford 4-((3-(5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2-yl)pyrrolidine-1-carbonyl)oxy)adamantane-1-carboxylic acid (20 mg, 55%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:11])[C:3]([NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:4].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1>C(O)(C)C.C(OCC)(=O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C@@H:2]([CH3:11])[C:3]([NH:5][CH2:6][C:7]([F:8])([F:9])[F:10])=[O:4])[CH:16]=[CH:15][N:14]=1
Reactant: C[C@H](N)C(=O)NCC(F)(F)F
Reactant: Clc1ccnc(Cl)n1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ccnc(Cl)n1)C(=O)NCC(F)(F)F

Procedure:
To a solution of (S)-2-amino-N-(2,2,2-trifluoroethyl)propanamide (FF) (1 g, 3.35 mol, 1 equiv.) in iso-propanol (10 mL), Huning's base (1.5 mL) was added, followed by 2,4-dichloropyrimidine (JJ). The resulting mixture was refluxed for 18 h. The reaction mixture was then diluted in ethyl acetate, washed with aqueous HCl 0.5 M and water, and dried over anhydrous Na2SO4. The crude oil was then purified by flash chromatography on silica gel, eluting with hexanes/ethyl acetate mixtures (100:0 to 0:100). The title compound HH was isolated as a white solid (600 mg, 63%).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:10]([CH3:12])[CH3:11])[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6].CN1CCOCC1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>O1CCCC1.C(OCC)(=O)C>[Cl:20][CH2:21][C:22]([NH:2][CH:3]([CH:10]([CH3:12])[CH3:11])[CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8])=[O:23]
Reactant: CC(C)C(N)C(O)C(F)(F)F
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)CCl)C(O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 3-amino-1,1,1-trifluoro-4-methyl-2-pentanol hydrochloride (20 g) in distilled tetrahydrofuran (480 mL) under nitrogen was added 4-methylmorpholine (21.8 mL) resulting in a white precipitate. A solution of chloroacetyl chloride (7.7 mL) in distilled tetrahydrofuran (40 mL) was added dropwise over 1 hour, and the mixture was stirred overnight. The mixture was diluted with ethyl acetate and filtered to remove undissolved solids. The filtrate was washed with 10% hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine. The solid that had been filtered was dissolved in water, the aqueous phase was extracted with ethyl acetate (twice), and the extracts were washed as the first extract had been. The organic phases were combined, dried, and evaporated to give 2-chloro-N-(3,3,3-trifluoro-2-hydroxy-1-isopropyl-propyl)acetamide as an oil (23.8 g); TLC: Rf =0.70, dichloromethane:methanol (95:5); MS: m/z=248(M+1 for 35Cl).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[O-2].[Mg+2].[S:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:11].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=O)C>CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2].ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([N:5]=[S:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:11])=[O:4]
Reactant: COC(=O)CS(=O)CC(=O)OC
Reactant: NC(=O)C(F)(F)F
Agent: [Rh+2]
Agent: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)CS(=O)(CC(=O)OC)=NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 98.4 %

Procedure:
Trifluoroacetamide (5.43 g, 2 eq), magnesium oxide (3.756 g, 4 eq), and rhodium(II) acetate dimer (309 mg, 0.03 eq) were placed in a 500 mL round-bottom flask. Dichloromethane (230 mL) was added followed by dimethyl 2,2′-sulfinyldiacetate (4.52 g, 23.3 mmol, 1 eq), followed by addition of diacetoxyiodobenzene in small portions (11.257 g, 1.5 eq). The mixture was stirred at room temperature for 7 hours. Following that, an additional 2.2 g of trifluoroacetamide was added followed by the addition of additional amount of rhodium(II) acetate dimer (˜150 mg) and diacetoxyiodobenzene (3.0 g). The reaction mixture was stirred further at room temperature overnight. The mixture was then filtered through a pad of celite and the pad was washed with MeOH—CHCl3 (1:5). The filtrate was concentrated and the oily residue was subject to column chromatography twice (from hexane to EtOAc-Hex 1:1) yielding dimethyl 2,2′-[N-(trifluoroacetyl)sulfonimidoyl]diacetate as a brown oil (7.0 g).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][C:5](=[O:11])[CH2:6][C:7](=[O:10])[CH2:8][CH3:9].[I-].[Na+].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)#[N:15]>CC(=O)CC.C(OCC)C>[O:10]=[C:7]([CH2:8][CH3:9])[CH:6]([C:5](=[O:11])[CH2:4][CH3:3])[CH2:20][C:19]1[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=1
Reactant: CCC(=O)CC(=O)CC
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCC(=O)C(Cc1ccc(C#N)cc1)C(=O)CC
Yield: 58 %

Procedure:
Sodium hydride (60% dispersion in oil, 3.43 g, 86 mmol) was added to a solution of 3,5-heptanedione (10 g, 78 mmol), in 2-butanone (200 ml), under nitrogen. A slight exotherm was observed during gas evolution. Sodium iodide (11.7 g, 78 mmol) was then added, followed by 4-cyanobenzyl bromide (15.29 g, 78 mmol) in 2-butanone (20 ml) and a precipitate was formed. The reaction mixture was heated at reflux for 16 hours. It was then filtered to remove the precipitate and concentrated under reduced pressure. The residue was stirred in dichloromethane (100 ml) and solid sodium bromide was removed by filtration. The dichloromethane filtrate was then washed with water (100 ml) and brine (100 ml). The organic layer was collected, dried over magnesium sulphate and concentrated under reduced pressure to give an orange solid. This was slurried in diethyl ether and filtered off to provide the title compound (11.01 g, 58%) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3): δ=0.98 (t, 6H), 2.29-2.35 (m, 2H), 2.42-2.52 (m, 2H), 3.19 (d, 2H), 3.97 (t, 1H), 7.25 (d, 2H), 7.56 (d, 2H); LRMS: APCl−: m/z 242 [M−H].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([OH:10])=[C:5]([CH3:11])[CH:4]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:10][C:6]1[C:5]([CH3:11])=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][C:7]=1[CH3:9])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(CO)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1c(C)cc(CO)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(hydroxymethyl)-2,6-dimethylphenol (P. Claus et al., Monatsh. Chem. 1972, 103(4), 1178–1193) (1.9 g) in acetonitrile (50 ml) was treated with ethyl bromoacetate (2.17 g) and caesium carbonate (4.24 g) and the mixture stirred at room temperature overnight. The solution was concentrated and the residue partitioned between ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound as a yellow oil.