Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[O:10][CH:11]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:44])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:5][CH:4]=1.[C:59]1(=[O:65])[O:64][C:62](=[O:63])[CH2:61][CH2:60]1>>[CH3:58][O:57][C:54]1[CH:53]=[CH:52][C:51]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][CH:11]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:12]2[N:13]([C:18](=[O:44])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:14][CH:15]([O:17][C:59](=[O:65])[CH2:60][CH2:61][C:62]([OH:64])=[O:63])[CH2:16]2)=[CH:56][CH:55]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCC=CCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Product: CCCCCCCCC=CCCCCCCCC(=O)NCCCCCC(=O)N1CC(OC(=O)CCC(=O)O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above described procedure, the amide 102f (2.4 g, 3 mmol) was treated with succinic anhydride and after work-up the amide was isolated as a foam (2.8 g, 99%) and this was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:10]([SH:13])[NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:21][CH2:22][CH2:23]Br.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:10]3[S:13][CH2:21][CH2:22][CH2:23][N:11]3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: Sc1[nH]nc(-c2cccc(Br)c2)c1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Yield: 50 %

Procedure:
5-(3-Bromo-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (60 mg, 0.22 mmol), 1,3-dibromopropane (22 ul, 0.22 mmol), K2CO3 (152 mg, 1.1 mmol) and dry DMF (5 ml) were reacted at room temperature for 16 hours. Water was added and the reaction extracted with ethyl acetate. The pooled organic extracts were washed with brine, dried over sodium sulphate and evaporated down. The crude material was purified by flash column chromatography eluting with ethyl acetate:hexane (1:1) to give a white solid (50% yield over two steps).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([OH:17])=[O:16].[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:12])([CH3:13])[CH3:14])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([O:17][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=1)=[O:16]
Reactant: CC(C)(C)c1ncc([C@H]2[C@H](C(=O)O)C2(C)C)cn1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ncc([C@H]2[C@H](C(=O)OCc3cccc(Oc4ccccc4)c3)C2(C)C)cn1
Reaction time: 16 h
Yield: 92.3 %

Procedure:
A mixture of trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl) pyrimidin-5-yl]cyclopropane carboxylic acid (500 mg), 3-phenoxybenzylbromide 552 mg), anhydrous potassium carbonate (304 mg) and acetone (10 cm3) was heated at the reflux temperature for 2 hours with stirring after which it was kept at the ambient temperature for 16 hours. After removing the solid precipitate by filtration the filtrate was concentrated by evaporation under reduced pressure. The residual oil was subjected to high performance liquid chromatography (Gilson) using a silica column and, as eluent, a mixture of dichloromethane (100 parts by volume) and ethyl acetate (2 parts by volume). The product, 3-phenoxybenzyl trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)-pyrimidin-5-yl]cyclopropane carboxylate (800 mg) was obtained as an oil and identification was confirmed by n.m.r. and infra red spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([Li])CCC.[CH2:27]1[O:29][CH2:28]1.O>C(COC)OC>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[C:5]([CH:28]([OH:29])[CH3:27])=[C:4]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:13]1
Reactant: CCCCCOc1cc(C2=NC(C)(C)CO2)ccc1OC
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Product: CCCCCOc1c(OC)ccc(C2=NC(C)(C)CO2)c1C(C)O
Temperature: -60 °C
Yield: 38.2 %

Procedure:
2-(4-Methoxy-3-pentyloxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (373 mg, 1.28 mmol, 1 eq) was dissolved in dimethoxyethane (7 ml). The solution was cooled to -60° C., and n-butyllithium (1.6M hexane solution)(1.76 ml, 2.82 mmol, 2.2 eq) was added dropwise. The mixture was stirred at said temperature for 1.5 hours. Ethylene oxide was added dropwise, and the mixture was stirred for 1.0 hour. The mixture was heated to room temperature, and further stirred for 2 hours. Water (50 ml) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=3/1-2/1) to give [6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methoxy-2-pentyloxyphenyl]ethanol (164 mg, 38.2%) as an oil.
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]([C:35](=[O:48])[NH:36][C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[Cl:47])[C:10]([O:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:14]=1)=[O:11].[S:49]([C:59]1[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=1)([C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)(=[O:51])=[O:50]>CN(C=O)C>[Cl:47][C:38]1[CH:39]=[CH:40][C:41]([C:43]([F:46])([F:45])[F:44])=[CH:42][C:37]=1[NH:36][C:35]([CH:9]([O:58][C:55]1[CH:54]=[CH:53][C:52]([S:49]([C:59]2[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=2)(=[O:51])=[O:50])=[CH:57][CH:56]=1)[C:10]([O:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:14]=1)=[O:11])=[O:48]
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)C(Cl)C(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)C(Oc2ccc(S(=O)(=O)c3ccc(O)cc3)cc2)C(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Reaction time: 1 h
Yield: 41 %

Procedure:
Triethylamine (12.12 g, 120 mmol) was added to a solution of the chloro-coupler (24.5 g, 40.5 mmol) from (e) and 4,4'-sulfonyldiphenol (40.5 g, 162 mmol) in dry DMF (130 ml) which has been degassed with nitrogen. After stirring at 45°-50° C. under nitrogen for 1 h, the suspension was cooled and poured slowly into cold water (300 ml) and conc. hydrochloric acid (10 ml), with rapid stirring. The whole mixture was extracted with ethyl acetate (500 ml) and the organic solution washed with 3N sodium carbonate (2×400 ml), 3N hydrochloric acid (300 ml), dried over MgSO4 and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (gradient elution from 20% ethyl acetate in petrol (b.p. 60°-80° C.) to 60% ethyl acetate in petrol (b.p. 60°-80° C.) followed by recrystallization from methanol to give a white solid (13.5 g, 41%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].O.[NH2:11][NH2:12]>CCO>[Cl:9][C:5]1[N:4]=[N:3][C:2]([NH:11][NH2:12])=[C:7]([NH2:8])[CH:6]=1
Reactant: NN
Reactant: Nc1cc(Cl)nnc1Cl
Solvent: CCO
Solvent: O
Product: NNc1nnc(Cl)cc1N
Temperature: 100 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a stirred suspension of 3,6-dichloropyridazin-4-amine (Step 112.1) (1.49 g, 9.09 mmol) in EtOH (15 mL) was added hydrazine hydrate (11.04 mL, 227 mmol) and the resulting mixture was heated up and stirred at 100° C. for 3 hr. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was triturated with water (25 mL) to afford the title product (478 mg, 3 mmol, 33% yield) as yellow solid. tR: 0.24 min (LC-MS 2); ESI-MS: 160 [M+H]+ (LC-MS 2); ESI-MS: 158 [M−H]− (LC-MS 2).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:11](=[O:23])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.C1C(=O)N([Br:33])C(=O)C1>C(#N)C>[Br:33][C:10]1[C:11](=[O:23])[N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:13]=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccn(Cc2cccc(F)c2)c(=O)c1)c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=C(Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 4-fluoro-N-[1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]benzamide (0.305 g, 0.89 mmol) in acetonitrile (7 mL) was added NBS (0.159 g, 0.89 mmol). The reaction mixture stirred at room temperature for 1.5 hours. The filtrate was removed under reduced pressure and the residue was purified by flash column chromatography (ethyl acetate/hexane 1:1 v/v). The fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 8.03 (m, 2H), 7.79 (d, 1H, J=7.6 Hz), 7.47 (d, 1H, J=8.0 Hz), 7.28 (m, 3H), 7.12 (m, 3H), 5.23 (s, 2H); ES-HRMS m/z 419.0202/421.0191 (M+H calculated for C19H14N2O2F2Br requires 419.0201/421.0183).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=2)[CH2:4][CH2:3]1.Br[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]2.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH3:34][C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[CH:33][C:24]=2[O:23][CH2:22][CH2:21][N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]4[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=4[CH:19]=3)[CH2:4][CH2:3]2)[N:29]=1
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Reactant: O=C1COc2ccc(CC3CCNCC3)cc2N1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(OCCN3CCC(Cc4ccc5c(c4)NC(=O)CO5)CC3)cccc2n1
Yield: 26.5 %

Procedure:
A mixture of 6-(4-piperidinylmethyl)-4H-benzo[1,4]oxazin-3-one hydrochloride (0.10 g, 0.35 mmol), 5-(2-bromoethoxy)-2-methylquinoline (0.11 g, 0.42 mmol), diisopropylethylamine (1 mL) and isopropanol (10 mL) was heated at reflux under argon for 48 h, cooled, then evaporated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (50 mL) and dichloromethane (3×30 mL) and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The resulting oil was purified by chromatography on silica eluting with 50% ethyl acetate-hexane followed by 0–25% methanol-ethyl acetate gradient elution, to give the title compound (0.04 g, 26%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.BrCCCC[C:22]1[CH:32]=[CH:31][CH:30]=[C:24]2[C:25]([NH:27][C:28](=[O:29])[C:23]=12)=[O:26]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:16][CH2:2][CH2:3][CH2:4][N:27]4[C:28](=[O:29])[C:23]5=[CH:22][CH:32]=[CH:31][CH:30]=[C:24]5[C:25]4=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 47.1 %

Procedure:
A mixture of 6 -fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.5 g, 25 mmol), 4-bromobutylphthalimide (8.0 g, 28.3 mmol, 1.13 eq), K2 CO3 (4.55 g, 32 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of the reaction, the mixture was filtered. The insolubles were washed with dichloromethane (200 ml). The organic solution was concentrated gradually to allow cystallization. The crude crystals (5.9 g) were collected. The mother liquor was concentrated to a solid (5.5 g,). Purification was by flash chromatography over a silica gel column. The product (3.8 g) thus purified was recrystallized from ethanol (70 ml) to give 2.48 g of N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide as white crystals, m.p.=144°-146° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1I>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Fc1cccc(Br)c1I
Reactant: Cc1ccc(S)c(C)c1
Product: Cc1ccc(Sc2c(F)cccc2Br)c(C)c1

Procedure:
Prepared from 2,4-dimethyl-benzenethiol and 1-bromo-3-fluoro-2-iodo-benzene.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:26][C:27]1[CH:28]=[CH:29][C:30]2[O:34][C:33](=[O:35])[NH:32][C:31]=2[CH:36]=1>CN(C=O)C>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([O:26][C:27]2[CH:28]=[CH:29][C:30]3[O:34][C:33](=[O:35])[NH:32][C:31]=3[CH:36]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: O=c1[nH]c2cc(O)ccc2o1
Reactant: NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(Nc2ccc(I)cc2F)cncc1Oc1ccc2oc(=O)[nH]c2c1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
100 mg of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (0.251 mmol, 1. eq.) were dissolved in DMF under a nitrogen atmosphere, then 245 mg of cesium carbonate (0.752 mmol, 3 eq.) and 45 mg of 5-hydroxy-1,3-benzoxazol-2(3H)-one (0.301 mmol, 1.2 eq.) were added. The resulting mixture was stirred at 50° C. bath temperature for 3 days. Then the mixture was partitioned between aq. NH4Cl solution (30 ml) and dichloromethane (30 ml). The phases were separated and the aqueouse layer was reextracted twice with dichloromethane/isopropanole (4:1, 30 ml each).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.I[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(I)cc1
Reactant: c1cn[nH]c1
Product: COc1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 1-iodo-4-methoxybenzene (468 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 340 mg (98% isolated yield) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[O:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:15][CH:12]2[CH2:13][CH2:14][O:10][CH2:11]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: OC1CCOC1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cnc(Cl)nc1OC1CCOC1
Temperature: 80 °C
Yield: 28.4 %

Procedure:
A flask was charged with a solution of 2,4-dichloro-5-fluoropyrimidine (1.0 g, 5.99 mmol) in N,N′-dimethylformamide (20 ml). Tetrahydrofuran-3-ol (0.63 m, 7.19 mmol) and cesium carbonate (3.32 g, 10.18 mmol) were added and the resulting mixture was heated to 80° C. overnight. Upon completion, the mixture was diluted with ethyl acetate (20 mL) and washed with 1:1 water:brine (3×40 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by CombiFlash (ethyl acetate/hexanes) provided 374 mg (1.7 mmol, 29%) of 2-chloro-5-fluoro-4-(tetrahydrofuran-3-yloxy)pyrimidine. MS APCI: [M+H]+ m/z 219.0.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([F:22])[CH:21]=1)[NH:18][CH:17]=[CH:16]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:39][NH:40]2)C1C=CC=CC=1)C>>[F:22][C:20]1[CH:21]=[C:13]([C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([NH:40][CH3:39])=[O:3])[CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[CH:16]2
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cc(F)c2[nH]ccc2c1
Product: CNC(=O)C=C(c1ccccc1)c1cc(F)c2[nH]ccc2c1
Yield: 59 %

Procedure:
3-(7-Fluoro-1H-indol-5-yl)-N-Methyl-3-phenyl-acrylamide LXXXII (120 mg, 59% yield) was prepared from 3-(7-fluoro-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described above for 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7](OC)=[O:8])[C@H:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:8][CH2:7][C@@H:5]1[CH2:6][C:2](=[CH2:1])[CH2:3][C@H:4]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a solution of methyl(+−)-trans-4-methylene-2-phenylcyclopentanoate (5.0 g, 23 mmol) from Step A in THF (30 mL) under nitrogen was added dropwise over 10 min 1M lithium aluminum hydride (LAH) in THF (23 mL). After 2 h at RT, the excess LAH was quenched by dropwise addition of ethyl acetate and the reaction was then poured into dilute aq. HCl. The mixture was extracted twice with ether and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (20-30% ethyl acetate in hexanes) to afford the title product (4.5 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5](Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1ccccc1C(Br)c1ccccc1
Product: CCOP(=O)(OCC)C(c1ccccc1)c1ccccc1C(F)(F)F

Procedure:
A solution of 2-(trifluoromethyl)benzhydryl bromide (25.2 g, 79.8 mmol) in triethyl phosphite (20.5 mL, 120 mmol), under N2, was heated at 155° C. for 16 hours. Excess triethyl phosphite was removed by distillation to give a yellow oil, 28.8 g. The crude product was chromatographed on a silica gel column. Elution with ethyl acetate/hexane (1:1) afforded analytically pure O,O-diethyl 2-trifluoromethylphenyl(phenyl)methylphosphonate as a pale yellow oil. 300 MHz 1H NMR (CDCl3): δ4.86 (d, 1H, J-26.18 Hz, PCH). MS: 373 (M+1).
Reaction SMILES: [Cl:1][C:2]([Cl:39])([Cl:38])[CH2:3][O:4][C:5](=[O:37])[N:6]([CH:16]1[CH2:20][CH:19]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH2:25][CH2:24]2)=[O:22])[NH:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15].[F:40][C:41]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:42]=1[CH:43]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:39][C:2]([Cl:1])([Cl:38])[CH2:3][O:4][C:5](=[O:37])[N:6]([CH:16]1[CH2:20][CH:19]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH2:25][CH2:24]2)=[O:22])[N:18]([CH2:43][C:42]2[CH:45]=[CH:46][CH:47]=[C:48]([F:49])[C:41]=2[F:40])[CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15]
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N(Cc3ccc(F)cc3F)C(=O)OCC(Cl)(Cl)Cl)CN2)CC1
Reactant: O=Cc1cccc(F)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(N(Cc3ccc(F)cc3F)C(=O)OCC(Cl)(Cl)Cl)CN2Cc2cccc(F)c2F)CC1
Reaction time: 0.33 h

Procedure:
A mixture of {5-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-pyrrolidin-3-yl}-(2,4-difluoro-benzyl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.078 g, 0.13 mmol), 2,3-difluorobenzaldehyde and acetic acid (cat.) in DCM (5 ml) was stirred for 20 min, and then NaBH(OAc)3 (0.041 g, 0.13 mmol) was carefully added. The reaction mixture was stirred overnight, and was concentrated to give crude product which was directly used for next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][C:22]([F:21])([F:32])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: CCc1cnc(NCCc2ccc(OC)c(Cl)c2)nc1
Product: CCc1cnc(N(CCc2ccc(O)c(Cl)c2)Cc2cccc(OC(F)(F)F)c2)nc1

Procedure:
Similarly prepared from N-[2-(3-chloro-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and 3-trifluoromethoxy benzyl bromide.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13]([NH:15][C@@H:16]1[C:21](=[O:22])[O:20][C:18](=[O:19])[CH2:17]1)=[O:14]>C(O)(=O)C>[CH:13]([NH:15][C@H:16]([C:21]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:22])[CH2:17][C:18](=[O:19])[OH:20])=[O:14]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CC(=O)O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a suitable reaction vessel at 45°-50°C., 34.6 g. (0.21 mole) of L-phenylalanine is added in about 45 minutes to a mixture of 30 g. (0.21 mole) of N-formyl-L-aspartic anhydride and 300 g. of glacial acetic acid. The resulting mixture is held for an additional 30 minutes, then cooled to 25°C. The resulting crystalline product is collected by filtration and washed with 50 g. of glacial acetic acid. The yield of N-formyl-α-L-aspartyl-L-phenylalanine is 40.5 g., m.p. 180°-182°C. TLC analysis of this product indicates no detectable β-form contamination.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Br:12]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1C(=O)O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1cc(F)ccc1CBr
Temperature: 78 °C
Yield: 96.7 %

Procedure:
Step 1 A suspension of 5-fluoro-2-methylbenzoic acid (500 mg, 3.24 mmol), N-bromosuccinimide (606 mg, 3.41 mmol) and benzoyl peroxide (47 mg, 0.195 mmol) in tetrachloromethane (10 mL) was heated at 78° C. for 4 h. The hot mixture was filtered and the filtrate was concentrated to provide crude 2-(bromomethyl)-5-fluorobenzoic acid as a white solid (730 mg), used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.81 (1H, dd, J=9.2, 2.9 Hz), 7.50 (1H, dd, J=8.5, 5.4 Hz), 7.23-7.30 (1H, m), 4.98 (2H, s).