Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:31][C:15]1[CH:16]=[C:17]([N:20]2[CH2:24][CH:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][O:13][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC(=O)NCC1CN(c2ccc(C(CO)Cn3cc([N+](=O)[O-])nc3Br)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NCC1CN(c2ccc(C3COc4nc([N+](=O)[O-])cn4C3)c(F)c2)C(=O)O1
Temperature: 50 °C
Reaction time: 4 h
Yield: 9.1 %

Procedure:
To a solution of crude N-(3-{4-[2-(2-Bromo-4-nitro-imidazol-1-yl)-1-hydroxymethyl-ethyl]-3-fluoro-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide (9 mg, 0.018 mmol) in DMF (1 mL) was added Cs2CO3 (18 mg, 0.054 mmol) at rt, and stirred for 4 h at 50° C. The reaction mixture was cooled to rt, diluted with EtOAc, washed with brine & water. The organic layers were separated, dried (MgSO4) and concentrated. Prep TLC (5% MeOH/CH2Cl2) provided 690 μg of pale yellow solid. ESI MS m/z 420 (M+H+).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[Br:14][CH2:15][CH2:16][CH2:17]Br.C(N(CC)CC)C>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][N:10]1[C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=[CH:9]1
Reactant: BrCCCBr
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2CCCBr)n(C)c1=O
Reaction time: 24 h
Yield: 76.6 %

Procedure:
A solution of theophylline (10.0 g, 0.0555 mol), 1,3-dibromopropane (11.6 ml, 23.1 g, 0.114 mol) and triethylamine (10.5 ml, 7.62 g, 0.0753 mol) in N,N-dimethylformamide (250 ml) was stirred at 60° C. overnight. The stirring was continued one day at room temperature. The solvent was evaporated under reduced pressure. The residue was suspended in CH2Cl2 and water. An emulsion was caused by a fine solid suspended in the mixture. The solid was filtered out and discarded. The aqueous layer was extracted three times with CHCl3. The combined organic layers were dried with MgSO4. Evaporation of the solvent under reduced pressure gave 7-(3-bromopropyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione (12.8 g, 77% yield).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:20]=[N:19][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:23][CH:22]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(C(F)(F)F)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-(trifluoromethyl)-pyridine-5-boronic acid (0.385 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 18 h to give 4-chloro-5,7-difluoro-3-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=359.0 (M+1).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[NH:14][C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O>[C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=3)[N:14]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2[nH]c3c(c2cc1OC)CC(OC(=O)c1ccccc1)CC3
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3cc(OC)c(OC)cc31)CC(OC(=O)c1ccccc1)CC2

Procedure:
The 3-benzoyloxy-6,7-dimethoxy-9-carbethoxymethyl-1,2,3,4-tetrahydrocarbazole was prepared by following an alkylation procedure similar to that described in Example 11 but using 17.6 g. of 3-benzoyloxy-6,7-dimethoxy-1,2,3,4-tetrahydrocarbazole (see Example 4) and 2.14 g. of sodium hydride (56% in mineral oil) in 200 ml. of dimethylformamide, and 8.4 g. of ethyl bromoacetate. The crude product in ethyl acetate was filtered through alumina, the filtrate was evaporated to dryness under reduced pressure and the residue was recrystallized from ethyl acetate to give 3-benzoyloxy-6,7-dimethoxy-9-carbethoxymethyl-1,2,3,4-tetrahydrocarbazole, m.p. 125°-127°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:30](=[O:32])[CH3:31])[CH:25]2[CH2:26][CH2:27][CH2:28]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CCC2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)C2CCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclobutylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C@H:4]([CH2:5][C@@H:6]([OH:60])[C@@H:7]3[C@@H:53]2[CH2:52][C@H:51]([OH:58])[C@@:50]2([CH3:59])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:49])[CH2:13][CH2:14][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:30]([Cl:31])=[CH:29][C:28]([NH:32][C:33](=[O:44])[C:34]([O:36]CC4C=CC=CC=4)=[O:35])=[CH:27][C:26]=3[Cl:45])=[CH:20][C:19]=2[CH:46]([CH3:48])[CH3:47])=[O:16])[CH2:3]1.[H][H]>C(O)C.[C].[Pd]>[OH:1][C@@H:2]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C@H:4]([CH2:5][C@@H:6]([OH:60])[C@@H:7]3[C@@H:53]2[CH2:52][C@H:51]([OH:58])[C@@:50]2([CH3:59])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:49])[CH2:13][CH2:14][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:26]([Cl:45])=[CH:27][C:28]([NH:32][C:33](=[O:44])[C:34]([OH:36])=[O:35])=[CH:29][C:30]=3[Cl:31])=[CH:20][C:19]=2[CH:46]([CH3:48])[CH3:47])=[O:16])[CH2:3]1
Reactant: [H][H]
Reactant: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)OCc3ccccc3)cc2Cl)ccc1OC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)O)cc2Cl)ccc1OC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
4- {4-[(2-benzyloxy-1,2-dioxoethyl)amino]-2,6-dichlorophenoxy}-2-isopropylphenyl 3,7,12(3α,5β,7α,12α)-trihydroxycholan-24-oate (260 mg) and 26 mg of 10% palladium carbon in 50 ml ethanol are treated with hydrogen on a Parr shaker. Catalyst is removed by filtering through celite and the fitrate is stripped to give 4-{2,6-dichloro4-[(2-hydroxy-1,2-dioxoethyl) amino]phenoxy}-2-isopropylphenyl 3,7,12(3α,5β,7α,12α)-trihydroxycholan-24oate, as an amorphane monohydrate, m.p. 180°-92° (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[NH2:24])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[NH:24][S:34]([CH3:33])(=[O:36])=[O:35])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3)c2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3)c2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.3 %

Procedure:
To a solution of 2-amino-4-(3-cyano-4-phenylpyrrole-1-yl)benzoic acid ethyl ester (0.050 g) and triethylamine (0.046 g) in dichloromethane (2 mL) was added methane sulfonylchloride (0.043 g) under ice-cooling, and this mixture was stirred at room temperature for 3 days. This reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=75/25) to give the title compound (0.015 g).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH3:15])[O:11][N:10]=2)=[CH:4][N:3]=1.[CH3:16][S-:17].[Na+]>C(O)(C)(C)C>[Cl:8][C:7]1[C:2]([S:17][CH3:16])=[N:3][CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH3:15])[O:11][N:10]=2)[CH:6]=1
Reactant: C[S-]
Reactant: CCc1cc(-c2cnc(Cl)c(Cl)c2)no1
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCc1cc(-c2cnc(SC)c(Cl)c2)no1
Reaction time: 3 h
Yield: 82.6 %

Procedure:
3-(2,3-Dichloro-5-pyridyl)-5-ethylisoxazole (0.71 g, 2.9 mmol) was dissolved in t-butanol (15 mL) and sodium methanethiolate (0.3 g, 4.3 mmol) added. The reaction mixture was heated under reflux with stirring for 3 hours, cooled, and poured onto ice. The resulting cream precipitate was collected by filtration, dissolved in dichloromethane (50 mL) and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure gave the desired product (0.61 g, 83%) as a cream solid, melting point. 59-62° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][C:10]([CH3:12])=O.[O-]S([O-])(=O)=O.[Mg+2]>[Pd]>[CH:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([CH3:12])[CH3:9]
Reactant: Nc1ccccc1O
Reactant: CC(C)=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(C)Nc1ccccc1O
Temperature: 100 °C

Procedure:
Into a 300 mL autoclave were charged 12 g (109.92 mmol) of o-aminophenol, 100 mL (79 g; 1.4 mol) of acetone, 0.6 g of Pd/C (Pd content: 5% by mass) and 30 g of MgSO4, and the contents of the autoclave were heated at 100° C. while stirring under a hydrogen pressure of 1.0 MPa. After the elapse of 1 h, the hydrogen absorption was ceased, and the reaction was terminated. The resultant reaction solution was subjected to suction filtration to remove Pd/C and MgSO4 therefrom, and the filtrate thus separated was concentrated and then mixed with water to crystallize a reaction product. The thus obtained reaction product was dried to obtain 2-(isopropylamino)phenol. As a result, it was confirmed that the yield of 2-(isopropylamino)phenol was 93%, and the oxygen absorption initiation time as an index of determining an oxidation-inhibiting property thereof was 370 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[C:21]2[CH:35]=[CH:36][CH:37]=[CH:38][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][CH:28]3[CH2:30][CH2:29]3)[C:23]3[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=3[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-L), the title compound was prepared. The reaction was monitored by tlc (Rf=0.30, 5% MeOH/CHCl3) and product was purified by chromatography (silica, 3% MeOH/CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncc(Br)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(Br)cnc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
To a solution of 5-bromo-2-methylpyridin-3-amine (10.7 g, 57.5 mmol) in dichloromethane (575 mL) was added acetic anhydride (12 mL, 126.5 mmol) at 0° C. followed by triethylamine (22 mL, 158 mmol). The mixture was allowed to warm to ambient temperature and stirred for 18 hours at which point a further equivalent of acetic anhydride (6 mL, 63 mmol) was added. The mixture was stirred at ambient temperature for a further 72 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (500 mL) and the organic phase washed with saturated aqueous sodium chloride (500 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. This solid was triturated with 30% ethyl acetate in hexanes to yield N-(5-bromo-2-methylpyridin-3-yl)acetamide as an off-white solid (8.28 g, 63%). 1HNMR (400 MHz, CD3OD, δ): 8.31 (s, 1H), 8.18 (s, 1H), 2.43 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(N)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.C(Cl)(=O)CCCCCCC/C=C\CCCCCCCC>>[CH2:13]([NH:27][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: NC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
N-Tetradecyl-N-(D-galactopyranosyl)amine was prepared from 30 g of D-galactose and 53 g of tetradecylamine as described in Example 44. The galactosylamine was reacted with oleoyl chloride according to the compound described in Example 11.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4](=[O:21])[CH:3]=1.P(Cl)(Cl)(Cl)=O.O.[OH-].[K+].CN(C)[CH:32]=[O:33]>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6](=[O:14])[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4](=[O:21])[C:3]=1[CH:32]=[O:33]
Reactant: Nc1cc(=O)n(-c2ccccc2)c(=O)n1-c1ccccc1
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Nc1c(C=O)c(=O)n(-c2ccccc2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A solution of 6-amino-1,3-diphenyluracil (10.0 g, 35.8 mmol) in dimethylformamide (100 mL) was cooled in an ice bath and phosphorus oxychloride (3.7 mL, 39.4 mmol) was dropped thereinto using a dropping funnel. The reaction mixture was stirred at room temperature for two hours and the reaction was stopped by adding 50 mL of water thereto. The pH was adjusted to 10 by a 1N solution of potassium hydroxide and stirring was carried out at room temperature for one additional hour. Crude crystals separated out therefrom were filtered and, after washing with 100 mL of water, the crude crystals were filtered. The resulting crude crystals were further recrystallized from hexane and ethyl acetate to give 6-amino-5-formyl-1,3-diphenyluracil (2.2 g) in a 40% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then benzylamine (56.4 mg, 0.526 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to afford the title compound (210 mg) as a yellow solid. LC-MS (ES) m/z=445 [M+H]+.
Reaction SMILES: Cl[C:2]1C=CC(OC2C=CC(NCC(N[C@@H](CC3C=CC=CC=3)C(NCCN3CCCC3)=O)=O)=CC=2)=CC=1.[Cl:38][C:39]1[CH:75]=[CH:74][C:42]([O:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]=[C:51]([NH:71][C:72]#[N:73])[NH:52][CH:53]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[CH2:54][C:55]([NH:57][CH2:58][CH2:59][N:60]3[CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:56])=[CH:46][CH:45]=2)=[CH:41][CH:40]=1>>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([O:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]=[C:51]([NH:71][C:72]#[N:73])[NH:52][C@@H:53]([CH2:65][C:66]3[CH:2]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH2:54][C:55]([NH:57][CH2:58][CH2:59][N:60]3[CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:56])=[CH:46][CH:45]=2)=[CH:74][CH:75]=1
Reactant: O=C(CNc1ccc(Oc2ccc(Cl)cc2)cc1)N[C@@H](Cc1ccccc1)C(=O)NCCN1CCCC1
Reactant: N#CNC(=Nc1ccc(Oc2ccc(Cl)cc2)cc1)NC(CC(=O)NCCN1CCCC1)c1ccccc1
Product: N#CNC(=Nc1ccc(Oc2ccc(Cl)cc2)cc1)N[C@H](CC(=O)NCCN1CCCC1)Cc1ccccc1

Procedure:
Prepared as in Example 8 from [(S)-1-benzyl-2-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (Example 27, step A) and 1-[4-(4-chloro-phenoxy)-phenyl]-3-cyano-thiourea (Example 32, step A). MS (electrospray): mass calculated for C30H33ClN6O2, 544.24; m/z found, 545.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.27–7.08 (m, 9H), 6.91 (t, J=9.4 Hz, 4H), 6.25 (br s, 1H), 4.35–4.26 (m, 1H), 3.35–3.28 (m, 1H), 3.25–3.17 (m, 1H), 2.99 (dd, J=13.5, 6.4 Hz, 1H), 2.7–2.68 (m, 1H), 2.52 (t, J=5.9 Hz, 2H), 2.49–2.41 (m, 4H), 2.41–2.35 (m, 1H), 2.26–2.18 (m, 1H), 1.74–1.69 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:21])C>S(=O)(=O)(O)O>[OH:21][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(OCC(F)(F)C(F)(F)F)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: Cc1c(OCC(F)(F)C(F)(F)F)ccnc1CO
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (2 drops) was added to a solution 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)-pyridine-1-oxide (2.5 g) in acetic anhydride (8 ml) and the mixture was stirred at 110° C. for 2 hours and then concentrated. The residue was dissolved in methanol (30 ml), 2 N aqueous sodium hydroxide (20 ml) was added, and the mixture was stirred at room temperature for 2 hours. After concentration, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was then distilled off, and te residue was applied to a silica gel (50 g) column. Elution with chloroform-methanol (10:1) and recrystallization from isopropyl ether gave 1.6 g of 2-hydroxymethyl-3-methyl-4-(2,2,3,3, 3-pentafluoropropoxy)pyridine as a brown oil.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].CN(C=O)C>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:22]1[CH:23]=[CH:24][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:20][CH:21]=1)[C:11]([CH3:12])=[CH:10]2
Reactant: COc1ccc2nc(Cl)c(C)cc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc3ccc(OC)cc3cc2C)cc1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 25 %

Procedure:
To a mixture of 2-chloro-6-methoxy-3-methylquinoline (100 mg, 0.482 mmol), 4-(methoxycarbonyl)phenylboronic acid (184 mg, 1.02 mmol), TEA (0.35 mL, 2.41 mmol), and PdCl2(dppf) (35 mg, 0.048 mmol) was added 2 mL of DMF under argon. The mixture was then stirred for 2.5 h at 120° C. in a microwave reactor. The crude mixture was then diluted with water (25 mL) and extracted with EtOAc (25 mL×2). The organics were washed with brine (50 mL), dried over sodium sulfate, and concentrated to yield 250 mg of crude material. The crude was purified via column chromatography with a gradient of 5% EtOAc in hexanes to 80% EtOAc in hexanes to yield 37 mg (25% yield) of methyl 4-(6-methoxy-3-methylquinolin-2-yl)benzoate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14]>C1C=CC=CC=1>[Cl:18][C:17]([Cl:20])([Cl:19])[CH2:16][O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:14]
Reactant: C1=CCNCC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC=CCC1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
124.5 g (1.5 mol) of 1,2,5,6-tetrahyropyridine are dissolved in 1,200 ml of benzene. 124 g of sodium bicarbonate are introduced into this solution and the mixture is then cooled to 0° under a nitrogen atmosphere and, at this temperature, is treated slowly dropwise in the course of 31/2 hours with a solution of 316 g (1.5 mol) of 2,2,2-trichloroethyl chloroformate in 250 ml of benzene. The resulting white suspension is subsequently stirred for a further 15 hours at 0° and then poured into 2,000 ml of ice-water. The benzene phase is separated off and the aqueous phase is extracted by shaking with twice 1,000 ml of methylene chloride; the combined organic phases are washed with 1 N hydrochloric acid and then with a saturated solution of sodium chloride, dried over sodium sulphate and evaporated under a water pump vacuum, whereupon 1-(β,β,β-trichloroethoxycarbonyl)-1,2,5,6-tetrahydropyridine is obtained as a slightly reddish oil.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH3:29][C:30]1[C:34]([CH:35]=O)=[C:33]([CH3:37])[N:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:31]=1>O1CCCC1>[CH3:2][O:3][CH:4]=[CH:35][C:34]1[C:30]([CH3:29])=[N:31][N:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:33]=1[CH3:37]
Reactant: Cc1nn(-c2ccccc2)c(C)c1C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=Cc1c(C)nn(-c2ccccc2)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To an ice-cold suspension of methoxymethyltriphenylphosphonium chloride (26.2 g, 74.9 mmol) in 300 mL tetrahydrofuran was added n-butyllithium (31 mL, 2.5 M in hexane). The mixture was stirred at 0° C. for 15 minutes and treated with 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carbaldehyde (7.5 g, 37.5 mmol, suspended in 150 mL tetrahydrofuran). The mixture was slowly warmed to room temperature over 2 hours and quenched by slow addition of a saturated aqueous sodium chloride solution. The resulting white precipitate was removed by filtration and the filtrate was extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to an oil, which was purified via silica gel column chromatography (0-20% ethyl acetate in heptane) to provide the title compound as a yellow oil (7.09 g, 31.1 mmol, 83% yield) as a mixture of E:Z isomers.