Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH3:2].[CH3:3][O:4][CH:5]([O:13][CH3:14])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S-:12])[N:7]=1.[Na+]>CO>[CH3:14][O:13][CH:5]([O:4][CH3:3])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:2])[N:7]=1
Reactant: CI
Reactant: COC(OC)c1ccnc([S-])n1
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccnc(SC)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Iodomethane (128 g, 902 mmol, 1.20 equiv.) was added carefully to the crude solution of sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2) (156 g, 751 mmol) in methanol (700 mL, 1.1 M) while maintaining the reaction temperature below 28° C. using an ice-water bath for cooling. The resulting mixture was stirred at room temperature for 16 h. After removal of the solvent under reduced pressure, the residue was diluted with water (300 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layer was concentrated under reduced pressure and the crude residue purified by passing through a short silica gel pad and washing with diethyl ether (200 mL) to afford 4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) as a brown oil (53.7 g, 150 g theoretical, 35.7%). LC-MS m/z 201 (M+1). Reference: WO 2006/0097341A1, pg 67.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[C:5]([NH2:8])=[N:6][CH:7]=1.I[C:12]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]([CH3:25])[CH:13]=1>C(N(CC)CC)C.CN(C)C=O.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH3:25])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: COc1cc2c(I)cn(C)c2cc1OC
Reactant: C#Cc1cc(Cl)cnc1N
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(C#Cc3cc(Cl)cnc3N)cn(C)c2cc1OC
Temperature: 20 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A suspension of 0.43 g of 5-chloro-3-ethynylpyridin-2-ylamine, 0.6 g of 3-iodo-5,6-dimethoxy-1-methyl-1H-indole (example 103-f), and 0.072 g of copper iodide, in a mixture of 60 ml of triethylamine and 30 ml of dimethylformamide, is degassed with argon for 15 minutes. 0.066 g of bis(triphenylphosphine) palladium(II) chloride is added to the above suspension. The mixture is agitated at around 20° C. for approximately 6 hours; 0.075 g of 5-chloro-3-ethynylpyridin-2-ylamine is added and the mixture is agitated at this same temperature for 2 days. The mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 100 ml of water and extracted with three times 100 ml of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (50/50 by volume)]. 0.44 g of 5-chloro-3-(5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl)pyridin-2-ylamine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>COCCOC>[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[S:27]
Reactant: COc1ccc(NC(=O)c2ccc(F)cc2)c(OC)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(NC(=S)c2ccc(F)cc2)c(OC)c1
Temperature: 85 °C
Reaction time: 4 h
Yield: 48.8 %

Procedure:
11 g (131 mmol; 4 equivalents) of NaHCO3 is added to 9 g (32.7 mmol) of N-(2,4-dimethoxyphenyl)-4-fluorobenzamide dissolved in 350 ml of 1,2-dimethoxyethane. 29 g (65.2 mmol; 2 equivalents) of phosphorus pentasulphide (P2S5) is then added by parts to the reaction medium which is maintained under stirring under an inert atmosphere of argon at 85° C. for 4 hours. 250 ml of a saturated solution of NaHCO3 are then added to the medium then the product is extracted with 3 times 200 ml of ethyl acetate. The combined organic phases are washed with twice 200 ml of a saturated solution of NaCl, then dried over sodium sulphate. The solvents are evaporated off under reduced pressure and the residue purified on a silica column (eluent: ethyl acetate/heptane mixture 1:4) in order to provide 4.65 g (yield=49%) of expected product.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:6])[NH2:4].CCN=C=NCCCN(C)C.[C:33](O)(=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:33]([NH:4][C@H:3]([C@H:5]([OH:6])/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][OH:1])(=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO)NC(=O)CCCCCCCCCCCCCCCCC
Yield: 75 %

Procedure:
To a solution of sphingosine (100 mg, 0.33 mmol) in CH2Cl2 (3 mL) was added EDCI (128 mg, 0.66 mmol) and DMAP (cat.). Under stirring, stearic acid (95 mg, 0.33 mmol in 10 mL CH2Cl2) was added dropwise over a period time of 16 h. The reaction was stirred under argon for 24 h at rt. Solvent was evaporated and the residue was applied to silica gel column chromatography (CHCl3:MeOH=9:1, Rf=0.43) to afford 8 as a white powder (140 mg, 75%). 1H NMR (600 MHz, CDCl3) δ 0.88 (t, J=6.8 Hz, 6H), 1.26-1.40 (m, 50H), 1.64 (t, J=7.2 Hz, 2H), 2.06 (dd, J=14.4, 7.2 Hz, 2H), 2.24 (t, J=7.2 Hz, 2H), 3.71 (m, 1H), 3.91-3.97 (m, 2H), 4.32 (m, 1H), 5.42 (dd, J=15.6, 6.6 Hz, 1H), 5.79 (dt, J=15.6, 6.6 Hz, 1H), 6.28 (d, J=7.2 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 14.3, 22.9, 26.0, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 32.2, 32.6, 54.7, 62.8, 74.9, 129.0, 134.6, 174.2. ESIMS calc'd for C36H71NNaO3 [M+Na]+ 588.53. found: 588.18.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
208 g of anthraquinone are stirred with 1,210 g of 99% strength nitric acid (molar ratio of nitric acid/anthraquinone = 19:1) for 26 minutes at 25°, resulting in a molar fraction of 0.87. To terminate the reaction, 566 g of 99% strength nitric acid are distilled off rapidly so that subsequently the molar fraction in the sump is 0.79. On adding 112 g of water, the temperature of the sump rises and on slow cooling the desired product separates out. (Molar fraction γHNO3 = 0.52). After centrifuging off at room temperature, rinsing with 75% strength nitric acid, washing until neutral and drying, 204 g of 89.4% strength 1-nitroanthraquinone are obtained (72% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14]C)=[O:13])[CH:6]=[CH:5]2.C[O-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]Cl)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C=O)C.CO>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]4)[CH2:30][CH2:31]2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: ClCCN1CCN(c2ccc(Cl)cc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)c1ccc2cc(OCCN3CCN(c4ccc(Cl)cc4)CC3)ccc2c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
2.11 g of methyl 6-hydroxy-2-naphthoate and 0.84 g of sodium methoxide are stirred under N2 at 40° C. for 30 min in 50 ml of DMF. 4.6 g of 4-(p-chlorophenyl)piperazinoethyl chloride are then added and the reaction mixture is stirred at 40° C. for 8 h. It is diluted with 350 ml of methanol and the precipitate which is deposited is filtered off with suction. It is dissolved in 80 ml of DMF and 10 ml of water, and the mixture is treated with 3.8 g of KOH and stirred at 100° C. for 10 h. The DMF is largely stripped off on a rotary evaporator, the residue is poured onto water and acidified, and the resulting precipitate is filtered off with suction. 2.5 g of 6-{2-[4-(4-chlorophenyl)-1-piperazinyl]ethoxy}-2-naphthoic acid are obtained; m.p. 197-199° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([C:24]2[C:29]([O:30][CH3:31])=[N:28][C:27]([P:32]([CH3:35])([CH3:34])=[O:33])=[CH:26][N:25]=2)[N:15]=1>>[CH3:35][P:32]([C:27]1[N:28]=[C:29]([O:30][CH3:31])[C:24]([C:16]2[N:17]=[C:18]([N:10]3[CH2:11][CH2:12][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]3)[C:19]([C:20]([F:22])([F:23])[F:21])=[CH:14][N:15]=2)=[N:25][CH:26]=1)([CH3:34])=[O:33]
Reactant: COc1nc(P(C)(C)=O)cnc1-c1ncc(C(F)(F)F)c(Cl)n1
Reactant: c1ccc(N2CCNCC2)cc1
Product: COc1nc(P(C)(C)=O)cnc1-c1ncc(C(F)(F)F)c(N2CCN(c3ccccc3)CC2)n1

Procedure:
This compound can be prepared by reacting 1-Phenylpiperazine with 4-chloro-2-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]-5-(trifluoromethyl)pyrimidine as described in Example 36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.N(OC(C)(C)C)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Cu]>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccccc1
Reactant: Nc1cccc(Cl)c1
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: Clc1cccc(-c2ccccc2)c1
Yield: 67.6 %

Procedure:
In a manner similar to Example 1, the reaction of 3-chloroaniline (38.3 g, 0.30 mole) with t-butyl nitrite (46.4 g, 0.45 mole) in the presence of copper powder (15.0 g, 0.24 mole) and 4Å molecular sieves (powdered, 15.0 g) in benzene (1650 ml) produced 3-chloro[1,1'-biphenyl] (38.4 g, 67.6% yield, bp 96°/0.15 mm) as an oil. When the experiment was repeated the yield was 65.7%
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:12](Cl)(=[O:15])[CH2:13][CH3:14].Cl>C(=S)=S>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(I)cc1
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 37.7 %

Procedure:
Iodobenzene (100 g, 0.49 mol) was taken in a dry 1 L 3 neck flask equipped with a N2 inlet and to it 200 ml of CS2 was added. The contents were cooled to 0-5° C. and then AlCl3 (80 g, 0.6 moles) and subsequently propionyl chloride (60 g, 0.64 mol) were added while keeping the temperature (internal) at 5-10° C. The contents were stirred for 24 hrs. The reaction mixture was poured into a 5 liter plastic beaker containing 1 L of 10% HCl+1 Kg of crushed ice. The resultant slurry was extracted with 1 L of ethyl acetate. The organic layer was separated and washed with 2×500 ml of water and 500 ml of brine. The organic layer was dried over sodium sulphate and concentrated at 40° C. to give 4′-iodopropiophenone (48 g, 38%).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[CH:7]=[N+:6]([O-])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:19][CH:12]1[C:13]2[C:8](=[CH:7][N:6]=[C:5]3[C:14]=2[CH:1]=[CH:2][CH:3]=[CH:4]3)[CH2:9][CH2:10][CH2:11]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cc2c(c3ccccc31)CCCC2
Product: CC(=O)OC1CCCc2cnc3ccccc3c21
Yield: 77 %

Procedure:
A solution of 7,8,9,10-tetrahydrophenanthridine N-oxide (Compound 4a) (1.23 g, 6.18 mmol) in acetic anhydride (50 mL) was heated to 100° C. for 20 hours, evaporated to dryness, dissolved in dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL). The aqueous layer was extracted with dichloromethane (2×50 mL), the combined organic layers were dried (Na2SO4), evaporated in vacuo, and the residue was purified by flash chromatography on silica eluting with Et2O to give pure Compound 5 (1.15 g, 77 percent) as a white crystalline solid: Rf =0.33 (ether); mp=128°-129° C. (from ether); IR (CDCl3) νmax 2970, 1728, 1241 cm-1 ; 1H NMR (500 MHz, CDCl3): δ 8.70 (s, 1 H, H-6), 8.08 (d, J=9.5 Hz, 1 H, H-4), 7.76 (d, J= 9.5 Hz, 1 H, H-1), 7.63 (t, J=7.2 Hz, 1 H, H-2 or H-3), 7.52 (t, J=7.2 Hz, 1 H, H-2 or H-3), 6.57 (bs, 1 H, CH--OAc), 3.02 (bd, J=17.5 Hz, 1 H, H-7), 2.88-2.80 (m, 1 H, H-7), 2.27 (bd, J=13.8 Hz, 1 H, H-9), 2.05 (s, 3 H, 0Ac), 2.01-1.88 (m, 3 H); 13C NMR (125 MHz, CDCl3): δ 170.2, 152.3, 147.5, 137.8, 131.8, 130.1, 127.9, 127.0, 126.8, 122.2, 64.5, 29.1, 27.8, 21.7, 18.4; MS (FAB+) m/e (relative intensity) 242 (M+H, 100), 182 (23); HRMS calcd. for C15H16NO2 (M+H) 242.1181, found 242.1181; Anal. calcd. for C15H15NO2 ; C, 74.67; H, 6.27; N, 5.80. Found: C, 74.59; H, 6.31; N, 5.82.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([C:50]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[O:51])[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([C:50]([N:52]6[CH2:53][CH2:54][O:55][CH2:56][CH2:57]6)=[O:51])[CH:45]=[CH:46][C:47]=5[O:48][CH3:49])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(C(=O)N2CCOCC2)cc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C(=O)N4CCOCC4)ccc3OC)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and (3-bromo-4-methoxy-phenyl)-morpholin-4-yl-methanone (59 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-methoxy-phenyl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-300) as a pale brown powder (67 mg, 100%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]=2[C:8](=[O:21])[NH:7][C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31]>CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]=2[C:8](=[O:21])[N:7]([CH2:30][CH3:31])[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCI
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CC)c(=O)c2c1ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-butyl-7-(phenylmethyl)-3,7-dihydro-1H-purine-2,6-dione (0.429 g, 1.24 mmol) and potassium carbonate (0.256 g, 1.85 mmol) were suspended in DMF (8 mL), iodoethane (0.113 mL, 1.42 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water, followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound; 1H NMR (400 MHz; CDCl3) δ: 0.96 (3H, t), 1.25 (3H, t), 1.36-1.45 (2H, m), 1.72-1.76 (2H, m), 4.05-4.13 (4H, m), 5.50 (2H, s), 7.32-7.40 (5H, m), 7.52 (1H, s); m/z 327 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:30].C1C([N+]([O-])=O)=CC=C([Cl-][C:41]([O-])=[O:42])C=1.[CH2:44]([NH2:49])[C:45]([CH3:48])([CH3:47])[CH3:46]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:41]([NH:49][CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:42])=[C:3]([F:30])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Reactant: CC(C)(C)CN
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.7 %

Procedure:
3-((4-(4-Amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (175 mg, 0.424 mmol) and 4-nitrophenylchloroformate (85 mg, 0424 mmol) were stirred in dichloromethane (2 mL) for 30 minutes. Neopentylamine (110 mg, 1.272 mmol) was added and the reaction stirred at room temperature for 2 hours. The reaction was concentrated under vacuum. The resulting residue was purified by acidic reverse phase HPLC to afford the title compound (26 mg).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]1[C:12]2[CH:11]=[C:10]([C:13]([O:15]C)=[O:14])[NH:9][C:8]=2[CH2:7][CH2:6]1.[OH-].[Li+].CO>C1COCC1>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]1[C:12]2[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[NH:9][C:8]=2[CH2:7][CH2:6]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(F)cc1F

Procedure:
The title compound was synthesized from methyl 4-(2,4-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.062 g, 0.213 mmol) and lithium hydroxide (0.045 g, 1.07 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 41 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.12 (m, 1H), 2.56 (m, 1H), 2.65 (m, 2H), 2.78 (d, J=7.37 Hz, 2H), 3.20-3.30 (m, 1H), 6.29 (s, 1H), 6.81-6.95 (m, 2H), 7.22 (m, 1H); 19F NMR δ ppm −116.13 (m), −116.30 (m); LCMS-MS (ESI−) 276.0 (M−H); HPLC (UV=99.0%), (ELSD=100%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 0 °C
Yield: 125.7 %

Procedure:
A solution of DIAD (11.4 mL; 55.0 mmol) in THF (15 mL) was added dropwise over 35 min to an ice-cold solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (10.06 g; 50.0 mmol), 4-chlorophenol (5.1 mL; 50.4 mmol) and triphenylphosphine (14.44 g; 55.1 mmol) in THF (40 mL). After 2.9 days at room temperature the solvent was removed on a rotary evaporator leaving a viscous liquid; hexanes was added then evaporated leaving a solid. Ether (25 mL), followed by hexanes (100 mL), was added and the solid was filtered and washed with hexanes. The filtrate was concentrated on a rotary evaporator leaving a golden, viscous liquid (19.6 g). The crude product was used as is. ESIMS 311.9/313.8 (25/10) [MH+], 296.9/298.8 (100/34) [MH+—C4H9+CH3CN], 255.9/257.8 (94/32) [MH+—C4H9], 212.0/214.0 (13/5) [MH+—C4H9—CO2].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].C1C(=O)N([Cl:18])C(=O)C1>CC(O)=O>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[Cl:18]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccc(N)c(F)c1
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(N)c(Cl)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mL) was stirred at 70° C. for approximately 16 h. The mixture was concentrated. H2O was added to the residue and the solid product was filtered off and washed (sat. NaHCO3 and H2O). To eliminate H2O, THF was added and removed under reduced pressure to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].N[C:34]1C=C(OC2C=CC=CC=2)C=CC=1C(NC1C=CC(OCCN2CCCC2)=C(OC)C=1)=O>>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:24][CH:23]=3)[N:1]=[CH:34]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2N)ccc1OCCN1CCCC1
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Product: COc1cc(-n2cnc3cc(-c4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1

Procedure:
Using 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenyl-benzamide [Example C5] in the manner of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide in Example C2, gave the title compound as a cream solid;
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:13](OCC)=[O:14].[H-].[Na+].O>C(COC)OC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([CH:13]=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CCc1ccco1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccco1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A mixture of ethyl 3-(2-furanyl)propionate (33.77 g) and ethyl formate (22.22 g) was added dropwise with stirring to a pre-cooled (0° C.) suspension of sodium hydride (50% in oil; 8.45 g) in dimethoxyethane (70 ml) maintaining the temperature below 0° C. throughout the addition. The reaction mixture was allowed to warm to room temperature then poured on to ice and water and extracted with ethyl acetate. The aqueous layer was acidified to pH 4 and re-extracted with ethyl acetate. These second ethyl acetate extracts were combined dried (MgSO4) and evaporated at reduced pressure to yield ethyl 3-(2-furanyl)-2-formylpropionate (19.0 g).