Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:13]([O-])([O-])=O.[K+].[K+].C.[I].CCOC(C)=O>CN(C=O)C>[CH3:13][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: C
Agent: [I]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 128.4 %

Procedure:
To a suspension of 20.0 g of 3-(trifluoromethoxy)phenol and 23.3 g of K2CO3 (anhydrous) in DMF (100 ml) was added 23.9 g of iodine methane under ice cooling, then the reaction mixture was warmed to room temperature, and was stirred at room temperature for 13 hours. To the reaction solution was added EtOAc (100 ml) and purified water (150 ml), and the resulting mixture was stirred for 30 minutes. After liquid separation, the aqueous layer was extracted with EtOAc (50 ml×2), the combined organic layer was washed with purified water (100 ml×3) and with saturated brine (50 ml) and dried overover MgSO4, then, the drying agent was separated by filtration, and the solvent was removed under reduced pressure to obtain 27.7 g of the title compound (crude form, yellow oil). The present compound was used in the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[S:25](Cl)(=[O:27])=[O:26]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[Cl:17])(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 123 mg of 2,4-dichloro-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.24 (m, 1H), 7.31 (m, 1H), 7.45 (m, 2H), 7.54 (m, 2H), 7.60-7.65 (m, 2H), 7.97 (d, 1H, J=8.4 Hz), 10.23 (s, 1H). MS: m/z 440.7 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=4[O:35][CH2:36][CH3:37])=[O:24])[NH:12][C@H:11]3[CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:5]2=[CH:4][CH:3]=1.CC[N:46]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C=O)C>[C:30]([C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:38][C:39]([CH3:40])([CH3:41])[CH3:42])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:43])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])=[C:27]([O:35][CH2:36][CH3:37])[CH:28]=1)(=[O:32])[NH2:46]
Reactant: CCOc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 80 °C

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-ethoxy-benzoic acid (0.1 g, 0.17 mmol) prepared in Example 130 in anhydrous DMF (2 mL) were added EDCI (64 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol), NH4Cl (89 mg, 1.67 mmol), and triethylamine (34 mg, 0.33 mmol) sequentially. The reaction mixture was heated at 80° C. for 1 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25-100% EtOAc in hexanes) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-2-ethoxy-phenyl)-amide as a off white solid (37 mg, 35%).
Reaction SMILES: [CH:1]([C:3]1(O)[CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].C[O:10][C:11]([CH3:13])=[CH2:12].OP(O)(O)=O.N#N>CC(OC)(C)C.C(N(CC)CC)C>[C:3]1(=[CH:1][CH2:2][CH2:12][C:11](=[O:10])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=CC1(O)CCCC1
Reactant: C=C(C)OC
Agent: N#N
Agent: O=P(O)(O)O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)CCC=C1CCCC1
Temperature: 125 °C
Reaction time: 14 h
Yield: 68.8 %

Procedure:
A 600 ml autoclave containing a mixture of 1-ethenyl-cyclopentanol (172.0 g; 1.54 mol), isopropenyl methyl ether (218.8 g; 3.04 mol), triethylamine (1.65 ml) and 85% H3PO4 (0.72 ml) was pressurized with N2 at 2 bar and heated up to 125° C. An increase of the pressure to 7 bar was observed. After 14 hours stirring, the autoclave was cooled down to room temperature and depressurized. MTBE (1.5 l) was added to the mixture, washed with H2O (4×25 ml) until neutral pH, dried (MgSO4) and concentrated. Distillation (61° C./0.1 torr) yielded 161.3 g (69% yield) of 5-cyclopentylidenepentan-2-one.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:12])[N:10]=[CH:11][C:6]2=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:4]=1.CCN(CC)CC.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C=O)C>[CH3:12][N:9]1[C:7]2=[N:8][C:3]([CH2:2][N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[CH:4][C:5]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[C:6]2[CH:11]=[N:10]1
Reactant: CN1CCNCC1
Reactant: Cn1ncc2c(-c3ccc([N+](=O)[O-])cc3)cc(CBr)nc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(Cc2cc(-c3ccc([N+](=O)[O-])cc3)c3cnn(C)c3n2)CC1
Temperature: 90 °C

Procedure:
900 mg of 6-bromomethyl-1-methyl-4-(4-nitro-phenyl)-1H-pyrazolo[3,4-b]pyridine (Intermediate 17.7; 2.59 mmol, 1 eq.) were dissolved in 13.5 mL DMF and treated sequentially with 0.54 mL Et3N (3.9 mmol, 1.5 eq.) and 0.35 mL methyl piperazine (3.11 mmol, 1.2 eq.). The reaction mixture was heated to 90° C. for 45 min, partitioned between CH2Cl2 and water, the aqueous layer was re-extracted and the combined organic layers were dried and concentrated in vacuo to yield the crude piperazine product, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13]Cl.[CH:15]([O-:17])=[O:16].[Na+].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13][O:17][CH:15]=[O:16]
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=COCc1c(Cl)ccc2cc(Cl)cnc12
Yield: 84 %

Procedure:
24.5 parts by weight of 3,7-dichloro-8-chloromethylquinoline and 13 parts by weight of sodium formate in 220 parts by weight of dimethylsulfoxide are heated for 6 hours at 100° C. The mixture is then cooled, water is added and the precipitated product is filtered off under suction and recrystallized from toluene. 21.5 parts by weight (84% of theory) of 3,7-dichloro-8-formyloxymethylquinoline of melting point 146° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[NH:15][CH3:16])=[C:4]([O:17][CH3:18])[CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([OH:25])=O>>[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([N:15]([C:9]1[CH:10]=[N:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:17][CH3:18])[CH3:16])=[O:25]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CNc1cnc(C)cc1-c1ccc(F)cc1OC
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N,6-dimethylpyridin-3-amine and 3-bromo-5-(trifluoromethyl)benzoic acid after a reaction time of 20 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (88%). MS (ESI): m/z=497.05 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br.[CH3:10][N:11]1[CH2:17][CH2:16][C:15]2=[CH:18][C:19](=[O:23])[C:20](=[O:22])[CH:21]=[C:14]2[CH2:13][CH2:12]1>CO>[OH:23][C:19]1[C:20]([OH:22])=[CH:21][C:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:17][CH2:16][C:15]=2[C:18]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(S)cc1
Reactant: CN1CCC2=CC(=O)C(=O)C=C2CC1
Agent: Br
Solvent: CO
Product: CN1CCc2cc(O)c(O)c(Sc3ccc(F)cc3)c2CC1

Procedure:
To a solution of 1.0 g. (0.0078 mole) of p-fluorothiophenol in 200 ml. of methanol was added portionwise 2 g. (0.0073 mole) of 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione hydrobromide (prepared as in Example 2) and the resulting mixture was stirred at room temperature under argon for 1 hour. The methanol was distilled from the reaction mixture in vacuo and the residue was partitioned between ether and water. The aqueous layer was extracted with ether and then made basic with ammonium hydroxide solution. The precipitate was filtered and the dried filtrate was chromatographed on silica using methanol/chloroform. The material eluted from the column was slurried with ether and filtered. Distillation of the ether gave 7,8-dihydroxy-6-(p-fluorophenylthio)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 164°-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([SH:18])[CH:14]=[C:15]([Cl:17])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:18][C:13]2[CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]([Cl:10])[CH:12]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Cl)cc(Sc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
Into a 300 ml three-necked glass flask equipped with a thermometer, a reflux condenser and a stirrer, 3,5-dichloroiodobenzene 22.6 g (82.8 mmol) and dimethylformamide 200 ml were added, and argon was passed through the solution for 2 hours and 15 minutes. Then, 3,5-dichlorothiophenol 14.8 g (82.6 mmol), potassium carbonate 22.8 g (165 mmol) and cuprous iodide 1.57 g (8.24 mmol) were added, which were reacted for 3 hours at 95 to 100° C. with stirring. After completion of the reaction, the reaction mixture was cooled down to room temperature and separated with the addition of water and hexane:ethyl acetate (1:1), and the organic layer obtained was dried with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained concentrate was purified by recrystallization, simple silica-gel column chromatography (eluent; hexane) to obtain bis(3,5-dichlorophenyl)sulfide 25.4 g as white solid (isolation yield; 95%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=O)[O:25]C(C)(C)C)[CH3:22])[C:15]=4[CH3:31])=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1.[N:33]1C=CC=CC=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24]([NH2:33])=[O:25])[CH3:22])[C:15]=4[CH3:31])=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1
Reactant: c1ccncc1
Reactant: Cc1c(OC[C@H](C)NC(=O)OC(C)(C)C)noc1-c1nc2cc(OCC3CC3)ccc2o1
Product: Cc1c(OC[C@H](C)NC(N)=O)noc1-c1nc2cc(OCC3CC3)ccc2o1

Procedure:
Using tert-butyl [(1S)-2-({5-[5-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-4-methylisoxazol-3-yl}oxy)-1-methylethyl]carbamate, and in the same manner as in Example 22 (using pyridine instead of triethylamine), the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.CN([CH:29]=[O:30])C>C1COCC1>[CH3:18][C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([CH:29]=[O:30])[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:20])[CH3:19]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)c2ncccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(C=O)c2ncccc2c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a THF (0.06 M) solution of 8-bromo-6-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)quinoline (1 eq.) was added at −78° C. n-butyl lithium (2.5 M in hexane, 2.1 eq.) dropwise over a period of 10 min. The resulting yellow solution was stirred at −78° C. for 15 min before DMF (2 eq.) was added dropwise over a period of 10 min. The now red solution was stirred at −78° C. for another 2 h before the reaction mixture was quenched with the addition of sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→3:7 (v/v) Hex:EtOAc) afforded the title compound as a yellow oil that solidified upon standing.
Reaction SMILES: [CH:1]1([C@H:7]([NH:37][C:38]([C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)=[O:39])[C:8]([NH:10][C@@H:11]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]([N:14]([C@H:16]2[CH2:20][N:19]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C@H:17]2[C:30]([OH:32])=O)[CH3:15])=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:65][CH:66]([CH2:75][CH2:76][CH3:77])[CH:67]([OH:74])[C:68]([NH:70][CH:71]1[CH2:73][CH2:72]1)=[O:69]>ClCCl.CCOC(C)=O>[CH:1]1([C@H:7]([NH:37][C:38]([C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)=[O:39])[C:8]([NH:10][C@@H:11]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]([N:14]([C@H:16]2[CH2:20][N:19]([C:21]([NH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:29])[CH2:18][C@H:17]2[C:30]([NH:65][C@@H:66]([CH2:75][CH2:76][CH3:77])[CH:67]([OH:74])[C:68]([NH:70][CH:71]2[CH2:72][CH2:73]2)=[O:69])=[O:32])[CH3:15])=[O:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C(=O)[C@@H](NC(=O)[C@@H](NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C)[C@H]1CN(C(=O)Nc2ccccc2)C[C@H]1C(=O)O
Reactant: CCCC(N)C(O)C(=O)NC1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCC[C@H](NC(=O)[C@@H]1CN(C(=O)Nc2ccccc2)C[C@@H]1N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Reaction time: 3 h
Yield: 49 %

Procedure:
A mixture of the product from Example 48, Part A (50 mg, 0.08 mmol), N-(3-dimethyl aminopropyl)-N′-ethylcarbodiimide hydrochloride (17 mg, 0.09 mmol), 1-hydroxybenzotriazole (12 mg, 0.09 mmol), Hunig's base (42 uL, 0.24 mmol) and 3-amino-N-cyclopropyl-2-hydroxyhexanamide (WO2002018369-A2; Example 119, cpd xiii′) (15 mg, 0.08 mmol)) in dichloromethane (5 mL) was stirred for 3 hours and diluted with 100 mL EtOAc, washed with 10 mL 1 M H3PO4, 10 mL 10% NaHCO3, 20 mL with brine, dried (MgSO4), and concentrated to give the title compound (31 mg, 49%). MS (ESI+) m/z=790.7 (M+H)+.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:52])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]5[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C@@H:40]([CH3:51])[CH2:39]5)[CH:32]=4)[CH:30]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)C.[H-].[Na+].[CH3:55][O:56][CH2:57][CH2:58]Br>CN(C=O)C>[F:52][C:28]1[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:51])[CH2:39]3)[CH:32]=2)=[CH:30][C:25]([CH2:24][N:23]([CH2:58][CH2:57][O:56][CH3:55])[C:21](=[O:22])[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:16]=2)=[CH:26][CH:27]=1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN(Cc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1)C(=O)c1cccc(CC2CCNCC2)c1
Yield: 27.3 %

Procedure:
Following the general procedure outlined in Example 66, 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[(1-([(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (76.1 mg, 0.106 mmol), NaH (8.29 mg, 0.345 mmol) and 2-bromoethyl methyl ether (0.015 mL, 0.160 mmol) in DMF (1.0 mL) were reacted to give the desired product (16.6 mg, 27.2%). EI-MS m/z 573(M−H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[NH:13])[CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[Na].Cl[CH2:18][CH:19]([OH:28])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[OH:28][CH:19]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[NH:13])[CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: N=C1CC(=O)Oc2cc(O)ccc21
Reactant: OC(CCl)COc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: N=C1CC(=O)Oc2cc(OCC(O)COc3ccccc3)ccc21
Yield: 91.7 %

Procedure:
To a warm stirred suspension of 3,4-dihydro-7-hydroxy-4-iminocoumarin (17.7 g; 0.1 mole) in dry DMF (75 ml) was added sodium hydride (2.4; 0.1 mole) portionwise and the mixture refluxed for 1.5 hours to complete formation of the sodium salt. A solution of 1-chloro-3-phenoxy-2-propanol (18.7 g; 0.1 mole) in dry DMF (10 ml) was added dropwise at reflux and the mixture stirred at reflux for an additional 4 hours. The solvent was removed in vacuo and water (200 ml) added to the residue. The yellow solid was filtered off, washed well with water and dried in vacuo over P2O5 to give 30.0 g (92%) of crude product which was suitable for most purposes. Recrystallisation from ethyl acetate gave material of m.p. 213°-214°; νmax (mull) 3320, 3200, complex carbonyl region 1690-1590 cm-1, τ(DSMO); 5.82(5H, m); 5.35(2H, broad exchangeable s); 4.85(1H, s); 3.20-2.52(8H, m with 1 proton removed after D2O exchange); 2.02(1H, d,) (Found; C, 64.52; H, 5.26; N, 3.78; C18H17NO5 0.5H2O requires; C, 64.28; H, 5.39; N, 4.16%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([NH2:21])([CH3:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:13]=2)[NH:8][CH:7]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.CO>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1([CH3:20])[CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:13]=3)[NH:8][C:7]=2[CH:27]([C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([OH:23])[CH:25]=2)[NH:21]1)=[O:22]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCOc1ccc2[nH]cc(CC(C)(N)C(=O)OC)c2c1
Solvent: ClCCl
Solvent: CO
Product: COCCOc1ccc2[nH]c3c(c2c1)CC(C)(C(=O)OC)NC3c1cccc(O)c1
Temperature: 25 °C
Yield: 14.2 %

Procedure:
To a solution of (+/−)-2-amino-3-[5-(2-methoxy-ethoxy)-1H-indol-3-yl]-2-methyl-propionic acid methyl ester (800 mg, 2.60 mmol) and 3-hydroxybenzaldehyde (383 mg, 3.14 mmol, 1.2 equiv) in dry dichloromethane (20 ml) trifluoroacetic acid (200 μl, 2.6 mmol, 1 equiv) is added and the mixture is stirred under argon at room temperature. When TLC indicated the disappearance of the starting material (1 day), a little methanol is added to dissolve the precipitated product. Then it is diluted with CH2Cl2 (250 ml) and washed with 2 M aqueous HCl, aqueous NaHCO3 and water, dried, and concentrated. Column chromatography (dichloromethane-ethyl acetate, 7:1→5:1) of the residue gives (1RS,3SR)-1-(3-hydroxy-phenyl)-6-(2-methoxy-ethoxy)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (839 mg, 78%) and (1RS,3RS)-1-(3-hydroxy-phenyl)-6-(2-methoxyethoxy)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (152 mg, 14%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=2[F:39])=[O:30])=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[O:17])[CH:12]=2)[CH:6]=1.[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=2[F:39])=[O:30])=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH:12]=2)[CH:6]=1
Reactant: COC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCC(=O)O)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoate (82 mg, 0.15 mmol) in a mixture of THF/MeOH (10 ml/10 ml) was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for 2 hours and poured into 100 ml of water. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoic acid as white solid. Yield: 70 mg, 88%.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.CC[Mg+].[Br-].Br[C:31]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(Cl)Cl.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:41][C:40]1[C:31]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=2)=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)c1cccc(F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cccc(F)c1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.1 %

Procedure:
To a stirred solution of 4-iodo-1-trityl-1H-imidazole (436 mg, 1.0 mmol) in anhydrous THF (6 mL) was added EtMgBr (3.0 M in THF, 1.20 mmol, 0.40 mL) under an atmosphere of N2. The resulting solution was allowed to stir for 90 min and ZnCl2 (0.5 M in THF, 2.40 mL, 1.20 mmol) was added. The resulting white suspension was allowed to stir for 90 min and a solution of methyl 2-bromo-3-fluorobenzoate (280 mg, 1.20 mmol) in THF (1 mL) was added followed by the immediate addition of Pd(PPh3)4 (58 mg, 0.05 mmol). The reaction mixture was allowed to stir at 90° C. for 18 h under an atmosphere of N2. After cooling to room temperature, the solution was diluted with CH2Cl2 (20 mL) and the organic layer was washed with an EDTA (aq) buffer (pH=9) (2×5 mL) and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to afford the desired product as yellow oil (190 mg, 41%). 1H NMR: 3.93 (s, 3H), 7.12-7.59 (m, 18H), 7.56 (s, 1H), 7.73-7.75 (m, 1H).