Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2(O)[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.O=S(Cl)[Cl:25]>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1)[Cl:25]
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)cccc32)n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C2(Cl)OC(=O)c3c(Cl)cccc32)n1

Procedure:
A mixture of 0.7 g of 7-chloro-3-hydroxy-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide, 30 ml of CCl4, 2 ml of SOCl2 and 4 drops of DMF are refluxed at 60° for 11/2 hrs. The mixture is then cooled, excess SOCl2 and CCl4 removed on a rotovaporator. The residue is diluted with 20 ml of CH2Cl2 and added to a stirred mixture of 10 ml of methanol and 2 ml of diethylamine. After 21/2 hrs the mixture is stripped on a rotovaporator to remove excess CH2Cl2 and methanol and the residue partitioned between CH2Cl2 (50 ml) and water (50 ml). The organic phase is separated, concentrated and the gummy residue flash chromatographed over silica gel using 80/20 hexane/ethyl acetate (500 ml), 60/40 hexane/ethyl acetate (500 ml) (28 fractions×50 ml). Fractions 18 to 20 yielded title compound a) and fractions 11 to 16 the compound b).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].C(O)=O.C(N(CC)CC)C.Cl>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccc(Cl)cc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: OC(CCl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
2-Chloro-4′-chloroacetophenone (189.6 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (2.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, 1 M hydrochloric acid (1.2 ml) was added, and the reaction product was extracted with ethyl acetate (2 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a desired compound, (+)-2-chloro-1-(4′-chlorophenyl)ethanol (172.8 mg; yield: 90.2%; optical purity: 91.6% ee).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:25]2[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][N:26]=2)[C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(C(C)(C)C)(C)C.Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][O:16][C:15]2[N:14]([C:25]3[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][N:26]=3)[N:13]=[CH:12][C:11]=2[CH2:10][CH2:9][OH:8])=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccnc(-n2ncc(CCO)c2OCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a mixture of 2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile (60 mg, 0.13 mmol, PREPARATION 8) in THF (5 mL) was added 3N HCl (1 mL) at 0° C. The reaction mixture was stirred for 2 h at r.t. Cooled to 0° C., added ethyl acetate, water and acidified with NaHCO3 to pH=8, and the mixture was then extracted with ethyl acetate and concentrated to afford the title compound (40 mg, 91%). [M+H] Calc'd for C18H15FN4O2, 339. Found, 339.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.C[Sn](C)(C)[C:22]1[CH:28]=[CH:27][C:26](=[O:29])[C:25]([O:30][CH3:31])=[CH:24][CH:23]=1.[Sn]>O1CCOCC1.[Pd].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[C:22]1[CH:28]=[CH:27][C:26](=[O:29])[C:25]([O:30][CH3:31])=[CH:24][CH:23]=1
Reactant: COc1ccc([Sn](C)(C)C)ccc1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: [Sn]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)ccc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A slurry of (S)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide described above (4.200 g, 11.11 mmol) and trimethyl(4-methoxy-5-oxo-1,3,6-cycloheptatrien-1-yl)tin (4.150 g, 13.88 mmol) in 1,4-dioxane (50 mL) was degassed by repeated evacuation and filling with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (0.545 g, 0.78 mmol) was added, the reaction again degassed, and then the mixture was brought to reflux under nitrogen. After 3 h TLC revealed some of the iodide still remained. Additional tin reagent (0.400 g, 1.34 mmol) and palladium catalyst (0.100 g, 0.14 mmol) were added and the mixture refluxed for 4 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 20% methanol/chloroform, filtered through Celite and concentrated in vacuo. The crude solids were triturated with dichloromethane/diethyl ether, the solids filtered, washed with diethyl ether and dried in vacuo to give 4.200 g (98%) of the title compound. The following characteristics were noted:
Reaction SMILES: [I-].[Na+].I.[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>O1CCOCC1>[CH2:4]([N:11]1[CH2:20][CH2:19][C:18]2[C:17]([NH:22][C:23]3[CH:24]=[N:25][C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:16][CH:15]=[N:14][C:13]=2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: Nc1cnc2ccccc2c1
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(CN2CCc3c(ncnc3Nc3cnc4ccccc4c3)C2)cc1
Yield: 58 %

Procedure:
Sodium iodide (434 mg, 2.9 mmol) and hydriodic acid (0.4 mL, 47% aqueous solution) were added to the solution 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine pepare as in Example 1 (500 mg, 1.93 mmol) and 3-aminoquinoline (418 mg, 2.9 mmol) in dioxane (4 mL) and the reaction solution was treated in a microwave at 150° C. for 20 min before solvent was removed. Residue was suspended in water, solid sodium carbonate was added to a pH>8, extracted by ethyl acetate and solvent was removed in vacuo. Residue was purified by column chromatography to yield the product as a beige solid (405 mg, 58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)nc5)cc34)cn2)c1
Yield: 30.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (70 mg, 0.126 mmol) was deprotected with TFA/DCM (1/5 ml). This afforded 17.5 mg (24.3% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.53 (s, 3H), 8.23 (s, 1H), 8.16-8.12 (dd, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.40-7.30 (m, 1H), 7.20-7.10 (m, 2H), 7.09-6.95 (m, 1H), 5.43 (s, 2H), 3.92-2.89 (m, 4H), 3.40-3.36 (m, 4H). MS: m/z=464.2 (M+1), HPLC: 97.79% in method A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5](O)=[O:6].C(N(C(C)C)CC)(C)C.C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([N:35]=[N+:36]=[N-:37])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
To a stirred solution of 3-bromo-5-iodo benzoic acid (5.0 g, 15 mmol) in methanol (30 mL) was added diisopropylethylamine (2.9 mL, 16.8 mmol) and diphenylphosphoryl azide (3.6 mL, 16.8 mmol). The reaction mixture was stirred for 12 hours at room temperature and then quenched with the addition of 100 mL water. A solid precipitated out. The solid was filtered, washed with water and dried to give 5.0 g (96%) of 3-bromo-5-iodo-benzoyl azide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.S(Cl)([Cl:15])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][Cl:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cc(Br)cc(CCl)c1
Reaction time: 1 h

Procedure:
To a stirring solution of (3-bromo-5-nitrophenyl)methanol (5.00 g; 21.5 mmol; Biogene Organics Inc) in DCM (65 mL) and NMP (9 mL) at RT was added dropwise thionylchloride (3.9 mL; 53.9 mmol). The mixture was allowed to react at RT overnight. Then, the mixture was poured into aqueous sodium bicarbonate solution/saturated aqueous sodium chloride solution/ice. The batch was stirred for one hour before it was extracted with ethyl acetate (2×). The combined organic phases were filtered using a Whatman filter and concentrated to give crude 1-bromo-3-(chloromethyl)-5-nitrobenzene, that was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])CCC.[CH3:17][O:18][CH:19]([O:28][CH3:29])[C:20](N1CCOCC1)=[O:21]>C1COCC1>[CH3:17][O:18][CH:19]([O:28][CH3:29])[C:20]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:21]
Reactant: COC(OC)C(=O)N1CCOCC1
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)C(=O)c1cnc2ccccc2c1
Reaction time: 0.25 h

Procedure:
3-Bromoquinoline (3.29 ml., 0.032 mol) was dissolved in 300 ml. THF and cooled to -78°. n-Butyllithium (13.6 ml. of 2.5M in hexane, 0.034 ml.) was added slowly and the mixture stirred 15 minutes at -75° to -78°. N-(Dimethoxyacetyl)morpholine (5.98 g., 0.032 mol) in 10 ml. THF was then added and stirring continued for 1.75 hours at the same temperature. The reaction was then quenched into 300 ml. saturated NH4Cl. The aqueous layer was separated and extracted 4×100 ml. ether. The organic layers were combined, dried over MgSO4O, stripped to yield title product, 7.0 g., bp 120°-123°/0.125 torr.
Reaction SMILES: C([N:11](CCCCCCCCCC)CCCN)CCCCCCCCC.[S:26]([OH:30])([OH:29])(=[O:28])=[O:27].CO[C:33](=[NH:35])[NH2:34]>>[S:26]([O-:30])([O-:29])(=[O:28])=[O:27].[NH2:34][C:33]([NH2:35])=[NH2+:11].[NH2:34][C:33]([NH2:35])=[NH2+:11]
Reactant: CCCCCCCCCCN(CCCN)CCCCCCCCCC
Reactant: O=S(=O)(O)O
Reactant: COC(=N)N
Product: NC(N)=[NH2+]
Product: O=S(=O)([O-])[O-]

Procedure:
Using the procedure of Process I, 708 g (2 moles) of 1-didecylamino-3-amino-propane are reacted with 236 g (0.96 moles) of O-methylisourea sulfate. The working up of this batch resulted in 623 g (70% of the theoretical yield) of guanidinium sulfate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].Cl[CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19]>CN(C)C=O>[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[O:14][CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19]
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: CCN(CC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1cc(N)c(Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
A cooled (0° C.) suspension of 60% sodium hydride/oil dispersion (1.40 g, 0.035 mole) in anhydrous dimethylformamide (60 ml) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (6.05 g, 0.030 mole) and stirred for 30 minutes at room temperature. 2-Chloro-N,N-diethylacetamide (5.40 g, 0.036 mole) was added, and the mixture was stirred at 100°-110° C. for 3 hours until gas chromatography indicated absence of 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester. The solution was cooled and added to ice water (350 ml), then extracted with ether (3×200 ml). The combined organic solution was dried (magnesium sulfate) and concentrated in vacuo. Filtration through alumina (eluted with 3% methanol/methylene chloride) and trituration from petroleum ethers (30°-60°) afforded 8.66 g (92%) of 4-amino-5-chloro-2-[2-(diethylamino)-2-oxoethoxy]benzoic acid methyl ester as a colorless solid; mp 97.5° -99.5° C. (ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[C:18]([C:20]1[CH:36]=[CH:35][C:23]([O:24][CH2:25][C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](Cl)=O)=[C:22]([F:37])[CH:21]=1)#[N:19].C([O-])(=O)C.[Na+]>ClCCl.C(O)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:28]([C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[CH2:25][O:24][C:23]3[CH:35]=[CH:36][C:20]([C:18]#[N:19])=[CH:21][C:22]=3[F:37])=[N:10][C:4]=2[CH:3]=1
Reactant: N#Cc1ccc(OCc2ccccc2C(=O)Cl)c(F)c1
Reactant: Nc1cc(F)c(F)cc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3[nH]2)c(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a mixture of 4,5-difluoro-benzene-1,2-diamine (501 mg, 3.47 mmol; CAS Reg. No. 76179-40-3) and triethylamine (0.64 ml, 4.74 mmol) in dichloromethane (10 ml) at 0° C. was added a solution of 2-(4-cyano-2-fluoro-phenoxymethyl)-benzoyl chloride (1.06 g, 3.65 mmol) in dichloromethane (15 ml) drop wise over 10 minutes. After stirring for 3 h at 0° C. the volatiles were removed in vacuo to give a yellow solid. The solid was dissolved in glacial acetic acid (15 ml), and sodium acetate was added to the solution, and the mixture was refluxed for 13 h. The reaction mixture was cooled to 25° C., evaporated in vacuo, and partitioned between dichloromethane and water. The biphasic mixture was cooled in an ice bath, and neutralized with solid potassium carbonate while maintaining vigorous stirring. The phases were separated, and the extraction was completed with additional portions of dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography over silica gel (15% ethyl acetate/n-hexane) to yield the desired compound as a brown solid (16%). MS (Turbo Spray): m/z=380.4 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH2:25]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:26]
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 27.5 °C
Yield: 98 %

Procedure:
To a slurry of sodium hydride (60% suspension in oil, 7.5 g) and dimethyl formamide (70 ml) was added a solution of the racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl)propionate of the formula (10) (40 g) obtained according to the procedure described in step (iii) above in dimethylformamide (105 ml) at 5-10° C. over a period of 15-30 minutes. The temperature was allowed to attain room temperature and maintained at the same temperature for 1-3 h. Ethyl iodide (36 g) was added slowly by maintaining the temperature at 25-30° C. over a period of 2-3 h. The progress of the reaction was monitored by TLC. After completion of the reaction the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with water and the solvent was removed under reduced pressure to afford the title compound of the formula (12a) (47-48 g, 98-99%).
Reaction SMILES: [N:1]1([C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH:9]([NH2:16])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH2:35][C:36](O)=[O:37])[CH:27]=[CH:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:22]>>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH2:35][C:36]([NH:16][CH:9]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:37])[CH:27]=[CH:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:22]
Reactant: NC(CC1CCCO1)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Product: CCOC(=O)c1ccc(CC(=O)NC(CC2CCCO2)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
Prepared analogously to Example 19 from 2-piperidino-α-(tetrahydrofuran-2-yl-methyl)-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenyl-acetic acid.
Reaction SMILES: C1([O:7][CH3:8])C=CC=CC=1.C=O.[ClH:11].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:11][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:7][CH3:8]
Reactant: Cl
Reactant: Cc1ccccc1
Reactant: COc1ccccc1
Agent: C=O
Product: COc1ccccc1CCl
Temperature: 120 °C

Procedure:
Chloromethylanisole was prepared by placing 162 grams (1.5 mole) of anisole and 150 grams of toluene in a 1-liter round bottom flask which was equipped with a mechanical stirrer, thermowell and gas inlet. The gas inlet was connected by means of a glass tube to a 200 cc round bottom flask also equipped with a gas inlet and thermowell. The glass tube which extended from the smaller flask to the larger flask was surrounded by a heating tape. The 200 cc round bottom flask was charged with 64 grams (2.1 mole) of paraformaldehyde following which the flask was then heated and maintained at a temperature of 120° C. Hydrogen chloride gas was passed at a flow rate of from 200 to 300 cc/min. into the flask containing the anisole and toluene. Likewise, the depolymerized formaldehyde was also passed to the flask containing anisole and toluene at a rate which was sufficient to match the rate of hydrogen chloride addition and also at a rate which was sufficient to prevent repolymerization of the formaldehyde to paraformaldehyde. At the end of 4 hours, the hydrogen chloride gas flow was reduced to 20 ml/min. and thereafter was halted. The reaction product was recovered and subjected to gas-liquid chromatographic analysis which disclosed a 91% conversion of the anisole with a 96.7% selectivity to monochloromethylanisoles.
Reaction SMILES: CC(C)([O-])C.[K+].C([O:9][C:10](=O)[CH2:11][N:12]([C:14](=[O:30])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH3:13])C.O>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]2[C:10](=[O:9])[CH2:11][N:12]([CH3:13])[C:14]2=[O:30])=[CH:24][CH:25]=1
Reactant: CCOC(=O)CN(C)C(=O)Cc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CC(=O)C(c2ccccc2Oc2ccc(Cl)cc2)C1=O
Temperature: 27.5 °C

Procedure:
To a suspension of potassium tert-butoxide (88 g) in toluene (1000 mL) is added a solution of ethyl-N-[2-[2-(4-chlorophenoxy)phenyl]acetyl]-N-methylglycinate (250 g) in toluene (1000 mL), under nitrogen at 15-25° C. and the mixture is maintained for 12-15 hours at 25-30° C. Water (3000 mL) is added and the mass is maintained for 1-2 hours at 0-5° C. Organic and aqueous layers are separated and the organic layer is washed with water (1000 mL). Aqueous layers are combined and washed with ethyl acetate (2000 mL). The pH of combined aqueous layers is adjusted to 2-2.5 by addition of aqueous HCl (100 mL) at 0-5° C. The solid is collected by filtration and washed with water (200 mL), then is dried to afford the crude title compound. The crude compound is further purified by heating at reflux a solution of crude 3-(2-(4-chlorophenoxy)phenyl)-1-methylpyrrolidine-2,4-dione in toluene (3600 mL) for 30-60 minutes, followed by cooling to room temperature. Solid that forms is collected by filtration, washed with hexane (500 mL), and dried to afford a purified title compound. Yield: 130 g. Purity by HPLC: 99.48%.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:22])[CH2:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.Cl.ClC1C=CSC=1C(=O)CN.FC(F)(F)C1C=CC(C(Cl)=O)=CC=1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:22][C:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)=[N:9][CH:8]=1
Reactant: O=C(NCC(=O)c1sccc1Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: NCC(=O)c1sccc1Cl
Agent: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2ncc(-c3sccc3Cl)o2)cc1

Procedure:
N-(2-(3-Chloro-thiophen-2-yl)-2-oxo-ethyl]-4-trifluoromethyl-benzamide: The title compound was prepared from 2-(3-chloro-thiophen-2-yl)-2-oxo-1-ethylamine hydrochloride and 4-trifluoromethyl-benzoyl chloride by a procedure similar to Example 98a as a white solid (0.044 g, 30%). 1H NMR (DMSO-d6): 9.06 (m, 1H), 7.99 (m, 3H), 7.77 (d, J=8.4 Hz, 2H), 7.20 (d, J=9.0 Hz, 1H), 4.73 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.[CH2:20]([C:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:20]([C:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:1][CH2:2][CH2:3][O:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:9][CH:8]=1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)NOCCO)cc1
Reactant: COc1ccc(CC(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CC(OCCONC(=O)c2ccc(C(=O)C(C)(C)C)cc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2.8 grams (10.6 mmol) of N-(2-hydroxy-ethoxy)-4-pivaloylbenzamide in 5 ml of methylene chloride and 3 ml of pyridine at 0° C. are added 3.92 grams (12.7 mmol) of ρ-anisylchlorodiphenylmethane. The mixture is warmed to room temperature over two hours and then diluted with 40 ml of methylene chloride. This solution is washed with 50 ml of 10% sodium bicarbonate and 30 ml of brine, dried over magnesium sulfate and concentrated by evaporation. The residue is purified by column chromatography using 5:1 hexane/ethyl acetate as the eluent to obtain the protected product, N-(2-[ρ-anisyldiphenylmethyloxy]ethoxy)-4-pivaloylbenzamide.