Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]([F:27])([F:26])C(C1C=CC=CC=1)=O.CCOC(C)=O>CC#N.O>[F:26][CH:17]([F:27])[O:9][C:6]1[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][CH:7]=1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: CSc1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSc1ncc(OC(F)F)cn1
Temperature: 80 °C
Yield: 23.9 %

Procedure:
To a stirring solution of 2-(methylthio)pyrimidin-5-ol (from step B) (71 mg, 0.50 mmol) in CH3CN (2.5 mL) and water (2.5 mL) at room temperature under argon was added K2CO3 (0.69 g, 5.0 mmol) and followed by 2-chloro-2,2-difluoro-1-phenylethanone (286 mg, 1.5 mmol). The reaction tube was sealed and heated at 80° C. for 5 hours. The reaction was cooled to room temperature. EtOAc (10 mL) was added to the reaction mixture, which was washed with brine (15 mL×3). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 0% to 100% EtOAc/Hexanes. 23 mg (23% for three steps) of 5-(difluoromethoxy)-2-(methylthio)pyrimidine was obtained as an off white solid. MS (ESI) 193 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH:18]([Br:21])(Br)Br.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Br:21][C:18]1[CH:7]=[N:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2
Reactant: BrC(Br)Br
Reactant: Fc1ccc2cc[nH]c2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc2cc(Br)cnc2c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
6-Fluoroindole (500 mg, 3.70 mmol) was combined with benzyltriethylammonium chloride (44.4 mg, 0.185 mmol) and toluene (0.32 mL) was added. Bromoform (0.342 mL, 3.70 mmol) was added and the temperature was brought to 40° C. A solution of NaOH (1.110 g, 7.50 mmol) in water (2.22 mL) was then added over 15 minutes. This caused a very dark color to form. The reaction was stirred as a biphasic mixture at 40° C. for 16 h before cooling and partitioning between ethyl acetate and water. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave 3-bromo-7-fluoro-quinoline (171.9 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=2.1 Hz, 1 H) 8.33 (d, J=2.0 Hz, 1 H) 7.68-7.82 (m, 2 H) 7.39 (td, J=8.6, 2.5 Hz, 1 H); MS (M+1): 226.0.
Reaction SMILES: [Sn](Cl)Cl.[C:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=3)[N:16]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:15]=2[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].Cl.[OH-].[Na+]>CCO>[NH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)[C:15]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:14]2[C:11]1[CH:10]=[CH:9][C:8]([C:4]([CH3:5])([CH3:7])[CH3:6])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc([N+](=O)[O-])ccc2n1Cc1cccc(OC)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(N)ccc2n1Cc1cccc(OC)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Tin (II) chloride (8.5 g, 45 mmol) was added to a stirred solution of ethyl 3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-5-nitro-1H-indole-2-carboxylate (Example 28, 4.5 g, 9.3 mmol) in EtOH (24 mL). The mixture was heated (50° C.) until there was a homogenous solution and then concentrated hydrochloric acid (16 mL) was added. The reaction was stirred at 60° C. for 2 h and then cooled. The pH of the solution was adjusted to pH=12 using 1 M aqueous sodium hydroxide and then the product was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, and concentrated in vacuo to leave 2.8 g (67%) of crude product that was taken to the next reaction without as proceeded to the next step without further purification. Mass spectroscopy gave MH+=457.4 (exact mass calc'd for C29H32N2O4=456.24).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(O)(=O)C.[C:35](Cl)(=[O:38])[CH2:36][OH:37].C[O-].[Na+]>C(Cl)Cl.CO>[OH:38][CH2:35][C:36]([N:21]1[CH2:20][CH2:19][CH:18]([C:16]2[S:15][CH:14]=[C:13]([C:11]([N:1]3[C@@H:10]4[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]4)[CH2:4][CH2:3][CH2:2]3)=[O:12])[CH:17]=2)[CH2:23][CH2:22]1)=[O:37]
Reactant: O=C(Cl)CO
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: O=C(CO)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Reaction time: 1 h
Yield: 25.6 %

Procedure:
To a solution of cis-(octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-033) (0.061 g, 0.18 mmol) in DCM (1 mL) was added triethylamine (0.55 mmol) and glycolic acid chloride acetate (0.24 mmol). The reaction mixture was stirred for 1 hour, and then the solvent evaporated. Methanol (1 mL) and sodium methoxide (0.91 mmol) were added and the reaction mixture was stirred overnight. The solvent was removed by evaporation and the product was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.018 g). LCMS m/z 391.11 [M+H]+ RT=9.24 min (Analytical Method 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccccc2)c(F)c1
Yield: 95 %

Procedure:
To a solution of 2-fluoro-4-nitro-1-phenoxybenzene (3.2 g, 13.72 mmol, 1.00 equiv) and methanol (100 mL) was added 10% palladium on carbon (0.5 g) catalyst. The reaction mixture was stirred under 1 atmosphere of hydrogen at room temperature for 4 h. The catalyst was removed by filtration. The filtrate was concentrated under vacuum to give 2.65 g (95%) of 3-fluoro-4-phenoxybenzenamine as an off-white solid. 1H-NMR (300 MHz, CDCl3): δ 7.29-7.19 (m, 2H), 7.03-6.83 (m, 4H), 6.52-6.36 (m, 2H), 3.63 (s, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH:22]([CH2:26][NH2:27])[CH2:21]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH:22]([CH2:26][NH:27][C:12](=[O:14])[CH2:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])[CH2:21]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: COC(=O)c1cccc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
A mixture of [3-(methoxycarbonyl)phenyl]acetic acid (0.200 g), Intermediate 1 (0.284 g), 1-hydroxybenzotriazole (0.182 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.316 g) was stirred in dichloromethane (10 ml), and N,N-diisopropylethylamine (0.352 ml) was added to the solution. Stirring at 20° C. under nitrogen was continued for 8 h. The mixture was purified by solid phase extraction (2×10 g Varian Bondelut silica gel cartridges), eluting successively with one column volume of dichloromethane, chloroform, ether, ethyl acetate, acetone, acetonitrile and methanol, to give the title compound as a colourless gum, (0.266 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=S)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[N:20]([CH2:21][CH:22]([OH:25])[CH2:23][OH:24])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCC(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)CO)c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A mixture of N-{3-amino-2-[(2,3-dihydroxypropyl)amino]phenyl}-N′-(2,4-dichlorophenyl)thiourea (Reference Example 86; 1.71 g, 4.25 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.44 g, 12.8 mmol) in tetrahydrofuran (43 mL) was stirred at 50° C. for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give the title compound (687 mg, 1.87 mmol, 44%) as a colorless amorphous.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[CH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO>[N:1]1([CH2:6][C:7]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[CH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1cccc(C=C(Cn2ccnc2)c2nccs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(C=C(Cn2ccnc2)c2nccs2)c1

Procedure:
The product of step C) (2.6 g; 8 mmol) in solution in MeOH (60 ml) was treated with NaOH 2N, (8 ml; 16 mmol) at room temperature for 2 hours. After evaporation of the methanol, the residue was acidified to pH 6 with HCl 6N, to precipitate a solid which was washed with water and ether to give 3-(3-(imidazol-1-yl)-2-(thiazol-2-yl)-prop-1-enyl)benzoic acid as a mixture of E and Z isomers (2 g; 80%).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(O)(=O)CCC/C=C\CC=CCCCCC(O)=O.C(O)(=O)CC/C=C\CC=CCCCCCC(O)=O.C(O)(=O)/C=C\CC=CCCCCCCCC(O)=O.C(O)(=O)C/C=C\CC=CCCCCC(O)=O.C(O)(=O)CC/C=C\CC=CCCCC(O)=O.C(O)(=O)/C=C\CC=CCCCCCC(O)=O.C(O)(=O)C/C=C\CC=CCCC(O)=O.C(O)(=O)/C=C\CC=CCCCC(O)=O.C(O)(=O)/C=C\CC=CCC(O)=O.C(O)(=O)CC/C=C\CCCCC(O)=O.C(O)(=O)/C=C\CCCCC(O)=O>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CC/C=C\CC=CCCCCCCCC(=O)O
Agent: O=C(O)/C=C\CC=CCC(=O)O
Agent: O=C(O)/C=C\CC=CCCCC(=O)O
Agent: O=C(O)/C=C\CC=CCCCCCC(=O)O
Product: O=C(O)CCCC/C=C\CC=CCCCCCC(=O)O

Procedure:
cis-4, 7-hexadecadiene dioic acid; cis-5, 8-tetradecadiene dioic acid; cis-4, 7-tetradecadiene dioic acid; cis-2, 5-tetradecadiene dioic acid; cis-3, 6-dodecadiene dioic acid; cis-4, 7-dodecadiene dioic acid; cis-2, 5-dodecadiene dioic acid; cis-3, 6-decadiene dioic acid; cis-2, 5-decadiene dioic acid; cis-2, 5-octadiene dioic acid; cis-4-decene dioic acid and cis-2-octene dioic acid.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[S:18]([N:28]1[CH2:33][CH2:32][CH2:31][C@@H:30](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:29]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C1(C)C=CC=CC=1>[C:8]([C:7]([C@H:32]1[CH2:31][CH2:30][CH2:29][N:28]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=2)(=[O:20])=[O:19])[CH2:33]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](C(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
Diphenylacetonitrile (13.5 g) was added to a stirred suspension of sodium hydride (3.2 g of a 60% suspension in mineral oil) in anhydrous toluene (250 ml) and the mixture was heated under reflux for 2 hours. On cooling to room temperature, 1-tosyl-3-(R)-(+)-tosyloxypiperidine (23 g) was added in portions and the mixture heated under reflux for 4 hours. The mixture was diluted with toluene (200 ml) and washed with 10% sodium hydroxide (2×100 ml) and brine (100 ml) then dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with toluene containing ethyl acetate (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from ethanol to give the title compound, yield 16 g, m.p. 148°-150° C., [α]D25 -94.4° (c 1.0, CH2Cl2).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]2=[O:16])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:17][C:18]1[S:22][C:21]([C:23]([NH:25][CH2:26][C:27]#[CH:28])=[O:24])=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>CO.C(#N)C.[Cu]I>[Cl:17][C:18]1[S:22][C:21]([C:23]([NH:25][CH2:26][C:27]2[N:3]=[N:2][N:1]([C:4]3[CH:9]=[CH:8][C:7]([N:10]4[CH:15]=[CH:14][CH:13]=[N:12][C:11]4=[O:16])=[CH:6][CH:5]=3)[CH:28]=2)=[O:24])=[CH:20][CH:19]=1
Reactant: [N-]=[N+]=Nc1ccc(-n2cccnc2=O)cc1
Reactant: C#CCNC(=O)c1ccc(Cl)s1
Agent: [Cu]I
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CO
Product: O=C(NCc1cn(-c2ccc(-n3cccnc3=O)cc2)nn1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Azidophenyl)pyrimidin-2(1H)-one (2.4, 20 mg, 0.09 mmol) was dissolved in 5 mL methanol. To it were added 5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide (compound 1.4, 18 mg, 0.09 mmol), DBU (26 μL, 0.18 mmol) and CuI (17 mg, 0.09 mmol). The mixture was stirred for 2 hrs at RT, diluted with 30 mL acetonitrile, filtered through celite, concentrated in vacuo and subjected to prep HPLC to isolate the title compound. MS found for C18H13ClN6O2S (M+H)+ 413.0, 415.0 (Cl pattern).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:12])[CH2:8][CH:9]([CH3:11])[CH3:10].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23][CH2:24][CH2:25]Cl>CS(C)=O.O>[CH2:7]([NH:12][CH2:25][CH2:24][O:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: ClCCOc1ccc2ccccc2c1
Reactant: CC(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CCNCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and isoamylamine (0.24 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 6 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(isoamyl)-(2-(naphthalen-2-yloxy)-ethyl)amine, solid, m.p. 91° C., (yield 0.51 gm, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O-:11])=[O:10])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].[CH2:19](I)[CH3:20].O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O:11][CH2:19][CH3:20])=[O:10])[C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCI
Reactant: Nc1cccc(CC(=O)[O-])c1-c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc(N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium 2-amino-6-biphenylacetate is dissolved in dimethylformamide and the solution treated with ethyliodide. The solution is stirred at room temperature for about 3 hours, the solution added to water and the mixture extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulfate, concentrated under reduced pressure and crystallized to give ethyl 2-amino-6-biphenylacetate.
Reaction SMILES: Cl.[C:2]1([CH2:12][CH2:13][NH2:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:21]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22]1>O.C(Cl)(Cl)Cl>[C:2]1([CH2:12][CH2:13][NH:14][C:25]([CH:21]2[CH2:24][CH2:23][CH2:22]2)=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1cccc2ccccc12
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1cccc2ccccc12)C1CCC1

Procedure:
0.01 mol of N-[2-(1-naphthyl)ethyl]amine hydrochloride is dissolved in a water/chloroform (40: 60; vol/vol ) mixture, and 0.02 mol of potassium carbonate is then added with magnetic stirring. The reaction mixture is cooled in an ice bath, and 0.01 mol of cyclobutanecarbonyl chloride is then added dropwise with magnetic stirring.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C(O)(=O)C.[Br:17]Br>>[NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([Br:17])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: CNC(=O)c1cccc(F)c1N
Solvent: CC(=O)O
Product: CNC(=O)c1cc(Br)cc(F)c1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Amino-3-fluoro-N-methyl-benzamide (10.0 g, 59.5 mmol) was dissolved in acetic acid (100 mL, 176 mmol) and bromine (3.22 mL, 62.4 mmol) was added. The reaction was stirred at room temperature for 20 minutes and the precipitate was then collected by filtration and washed with ethyl ether. The white solid was dried overnight under high vacuum at 50° C. to obtain 2-amino-5-bromo-3-fluoro-N-methyl-benzamide; hydrobromide as a white solid (16.8 g, 86%). LCMS (m/e) 216 (M—NHCH3); 1H-NMR (d6-DMSO, 400 MHz) δ 8.49-8.38 (m, 1H), 7.83-7.46 (m, 3H), 7.54 (s, 1H), 7.43 (d, 1H, J=10.89 Hz), 2.72 (d, 3H, J=4.2 Hz); 19F-NMR (d6-DMSO, 400 MHz) δ 131.
Reaction SMILES: NC(C(O)=O)CC(C)C.[OH-].[Na+].BrC(C)C(Cl)=O.C(O)(=S)C1C=CC=CC=1.C([S:35][CH:36]([CH3:48])[C:37]([NH:39][C@H:40]([C:45]([OH:47])=[O:46])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:38])(=O)C1C=CC=CC=1.N[C@H](C(O)=O)CC(C)C>N>[SH:35][CH:36]([CH3:48])[C:37]([NH:39][C@H:40]([C:45]([OH:47])=[O:46])[CH2:41][CH:42]([CH3:43])[CH3:44])=[O:38]
Reactant: CC(C)C[C@H](NC(=O)C(C)SC(=O)c1ccccc1)C(=O)O
Agent: CC(Br)C(=O)Cl
Agent: CC(C)CC(N)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Product: CC(C)C[C@H](NC(=O)C(C)S)C(=O)O
Yield: 63.9 %

Procedure:
13.1g (0.10 mol) of DL-leucine was neutralized with 50 ml of 2N-NaOH solution and to the solution were simultaneously added dropwise 17.1g (0.10 mol) of 2-bromopropionylchloride and 50 ml of 2N-NaOH solution at room temperature over one hour while stirring and maintaining the reaction mixture in a slightly alkaline condition. After completion of the addition, the ice bath used was removed and the mixture was stirred at room temperature for 3 hours. Successively, to the mixture was added the filtrate which had been prepared by neutralizing 13.8g (0.10 mol) of thiobenzoic acid with 50 ml of 2N--KOH solution and filtering. The resulting mixture was stirred at room temperature overnight and then acidified with hydrochloric acid to form oil. After extraction of oil with ethyl acetate, the oil was purified by subjecting it to chromatography using a silica gel column to give 18.5g of N-(2-benzoylmercaptopropionyl)leusine as oil. 40 ml of concentrated aqueous ammonia was added to 6.0g of N-(2-benzoylmercaptopropionyl)leucine to allow the derivative of leucine to hydrolyze in a manner similar to that used in Example I to give 2.6g of N-(2-mercaptopropionyl)leucine, ##EQU10## (m.p. 77° - 84°C)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[C:11]([N+:28]([O-:30])=[O:29])=[C:10]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:9]=1.[F:37][CH:38]([F:50])[C:39]1[NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:41]=2[N:40]=1>CN(C=O)C.O>[F:50][CH:38]([F:37])[C:39]1[N:43]([C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[C:11]([N+:28]([O-:30])=[O:29])=[C:10]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[N:9]=2)[C:42]2[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:41]=2[N:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc(N3CCOCC3)c2[N+](=O)[O-])CC1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c(N2CCOCC2)n1
Reaction time: 60 h
Yield: 89 %

Procedure:
Powdered K2CO3 (1.305 g, 9.44 mmol) was added to a stirred suspension of tert-butyl 4-{[2-chloro-6-(4-morpholinyl)-5-nitro-4-pyrimidinyl]amino}-1-piperidinecarboxylate (U.S. Pat. Appl. Publ. No. 2009/0181963, the disclosure of which is incorporated herein by reference in its entirety) (1.047 g, 2.36 mmol) and 2-difluoromethyl-4-methoxy-1H-benzimidazole (Example 2) (608 mg, 3.07 mmol) in DMF (70 mL) at room temperature, and the mixture was stirred for 2.5 days. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration and dried. Recrystallization from CH2Cl2/MeOH gave tert-butyl 4-{[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-5-nitro-4-pyrimidinyl]amino}-1-piperidinecarboxylate (1.27 g, 89%): mp 229-231° C.; 1H NMR (CDCl3) δ 8.64 (d, J=7.7 Hz, 1H), 7.81 (dd, J=8.4, 0.6 Hz, 1H), 7.36 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.36 (m, 1H), 4.11 (m, 2H), 4.06 (s, 3H), 3.85 (t, J=4.9 Hz, 4H), 3.65 (t, J=4.6 Hz, 4H), 3.01 (t, J=11.5 Hz, 2H), 2.08 (m, 2H), 1.64-1.51 (m, 2H), 1.48 (s, 9H); Anal. Calcd. for C27H34F2N8O6: C, 53.6; H, 5.7; N, 18.5. Found: C, 53.35; H, 5.7; N, 18.8%.
Reaction SMILES: [Li+].[OH-].[C:3]([N:6]1[CH2:11][CH:10]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH:8]([C:19]([O:21]CC)=[O:20])[CH2:7]1)(=[O:5])[CH3:4].C(Cl)Cl.O>CO.C1COCC1>[C:3]([N:6]1[CH2:11][CH:10]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:9][CH:8]([C:19]([OH:21])=[O:20])[CH2:7]1)(=[O:5])[CH3:4]
Reactant: CCOC(=O)C1CC(CC2CCCCC2)CN(C(C)=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CC(CC2CCCCC2)CC(C(=O)O)C1

Procedure:
LiOH (2 N, 500 μL) was added to a solution of ethyl 1-acetyl-5-(cyclohexylmethyl)piperidine-3-carboxylate (180 mL, 0.61 mmol) in MeOH (1 mL) and THF (5 mL). After being maintained for two hours, the reaction was poured into a mixture of CH2Cl2 (25 mL) and H2O (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (10 mL). The aqueous layer was acidified to pH 1 with 1N HCl and extracted with CH2Cl2 (3×20 mL). The combined organic layers were sequentially washed with H2O (10 mL) and brine before being dried over Na2SO4. Concentration under reduced pressure provided the title compound as a colorless oil. MS m/z: 268.0 (M+1).