Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]=1[O:24][CH2:25][CH3:26])(C)C)(C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH2:25]([O:24][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][C:9]=1[OH:8])[CH3:26]
Reactant: CCOc1cc(C=CCc2ccccc2)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C=CCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a solution of tert-butyl(2-ethoxy-4-(3-phenylprop-1-enyl)phenoxy)-dimethylsilane (3.12 g, 8.46 mmol, 1.0 equiv.), in THF (17 mL), n-Bu4NF (10.2 mL, 10.2 mmol, 1.2 equiv., 1.0 M in THF) was added, and the mixture was stirred at 25° C. for 1 h. After addition of H2O, the aqueous layer was extracted with MTBE (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 95:5) to yield 1.60 g (74%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH3:14])[C:5]=1[CH2:6]O)[CH3:2].P(Br)(Br)[Br:16]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH3:14])[C:5]=1[CH2:6][Br:16])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOc1cccc(OCC)c1CO
Solvent: C1CCOC1
Product: CCOc1cccc(OCC)c1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 2,6-diethoxybenzyl alcohol (1.0 g, 5.2 mmol) in THF (10 mL) was added phosphorous tribromide (0.48 mL, 5.1 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 1 h. After quenching the reaction with water, the mixture was extracted with EtOAc. The combined organics were washed with brine and dried over Na2SO4. The solution was concentrated under reduced pressure to give 2,6-diethoxybenzyl bromide as a brown oil. Yield (1.3 g, 98%).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][O:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:20]=[CH:21][CH:22]=[CH:23]3)[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: Oc1ccc2ncccc2c1
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccc3ncccc3c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester Example 323, Step 1) and quinolin-6-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C22H23NO5 [M+H]+: 382.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18].O>C(OCC)(=O)C>[CH3:13][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=2)[CH2:2][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(Oc2cccc(CCl)c2)n1
Reactant: CCOP(OCC)OCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cccc(Oc2cccc(C)n2)c1)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
2-(3-(Chloromethyl)phenoxy)-6-methylpyridine (4.0 g, 17 mmol) from Step 2 was treated neat with triethylphosphite (3.67 mL, 21.4 mmol) and heated to 150° C. After 16 h, the reaction mixture was cooled to room temperature and partioned between water and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (30-60%, EtOAc:CH2Cl2) to afford the title compound (4.7 g, 82% yield) as a thick oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.[Br:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>>[Br:21][C:22]1[N:23]=[CH:24][N:25]([C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:3]=2)[CH:26]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Brc1c[nH]cn1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-difluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.5) (1.0 g, 3.24 mmol) and commercially available 4-bromo-imidazole (0.71 g, 4.86 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.98 g, 72%). MS (ISP) 420.9 [(M+H)+]; mp 147° C.
Reaction SMILES: [NH:1]=[C:2]([NH:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:3]>C(Cl)(Cl)Cl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[N:1]=[C:2]([CH3:3])[NH:4][N:5]=2)=[CH:8][CH:9]=1
Reactant: CC(=N)NNC(=O)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccc(Cl)cc2)n[nH]1
Yield: 21.9 %

Procedure:
6.10 g (28.8 mmol) 4-chloro-benzoic acid N′-(1-imino-ethyl)-hydrazide are heated to 180° C. for 30 minutes. After cooling 2.3 g product are obtained from the residue by recrystallisation in chloroform. Evaporation of the mother liquor and subsequent purification of the residue by chromatography (silica gel, petroleum ether/ethyl acetate=1:6) yield an additional 1.22 g of product. White solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:15](/[CH:16]=[CH:17]/[C:18]([CH3:31])([O:24]C2CCCCO2)[CH2:19][CH2:20][C:21]#[C:22][CH3:23])[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:4](=[O:32])[CH2:3]1>C(O)(=O)C.O.C1COCC1>[OH:1][C@H:2]1[C@H:15](/[CH:16]=[CH:17]/[C:18]([OH:24])([CH3:31])[CH2:19][CH2:20][C:21]#[C:22][CH3:23])[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:4](=[O:32])[CH2:3]1
Reactant: CC#CCCC(C)(/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O)OC1CCCCO1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC#CCCC(C)(O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
From 270 mg. of (13E)-(11R,15RS)-11-hydroxy-15-methyl-9-oxo-15-(tetrahydropyran-2-yloxy)-13-prosten-18-ynoic acid and 9 ml. of a mixture of glacial acetic acid/water/THF (65/35/10), 190 mg. of the title compound is obtained as an oil in the usual way.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>CC(O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[C:7]([F:13])[CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[CH:4][C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Cl
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2c(F)ccc(F)c2c1Nc1cccc(Br)c1
Yield: 40.5 %

Procedure:
The reaction mixture of 200.0 mg (0.74 mmol) of 4-chloro-3-ethoxycarbonyl-5,8-difluoroquinoline and 155.1 mg (0.88 mmol) of 3-bromoaniline in 4.0 mL of 2-propanol was refluxed for 2 h and cooled down. The yellow precipitate was filtered, washed with cold 2-propanol, and dried in oven at 30° C. overnight to give 122.0 mg (40%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=[O:9])([CH3:6])[CH3:5].[OH-].[Na+]>C1COCC1>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:29])=[O:2])=[O:9])=[CH:27][CH:26]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ccc2ccccc2c1OCc1ccc(Br)cc1)C(=O)O
Yield: 75.2 %

Procedure:
A solution of 96 mg 2-{[1-(4-bromo-benzyloxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester in 1 ml dry THF was treated with 0.2 ml of 2 M aqueous sodium hydroxide. After 4 h at 60° C. the reaction was concentrated, the residue was taken up in 3 ml of water, treated with 2 M hydrochloric acid, and the resulting precipitate was collected by filtration and purified by RP-HPLC to yield 70 mg 2-{[1-(4-bromo-benzyloxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid.
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[C:12](#[N:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC1C=CC=CC=1Cl>>[C:13]1([C:12]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:19]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1nsc(=O)o1
Reactant: N#Cc1ccccc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nsc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 3 %

Procedure:
A mixture of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate (U.S. Publication No. 2005/0096362) (1.5 g, 8.56 mmol) and benzonitrile (4.37 ml, 42.8 mmol) in 1,2-dichlorobenzene (15.42 ml, 137 mmol) was heated to 160° C. for 4 days. The reaction was then cooled down to RT and the solvent was evaporated by heated the reaction at 75° C. at maximum vacuum. The residue was purified on silica gel chromatography (100% CH2Cl2 to 3% EtOAc in CH2Cl2) to provide the title material (0.064 g, 3%). LC (Method B): 2.021 min. HRMS (ESI) calcd for C11H11N2O2S [M+H]+ m/z 235.0541, found 235. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.01-8.09 (m, 1H), 7.49-7.59 (m, 2H), 4.56 (q, J=7.17 Hz, 1H), 1.50 (t, J=7.24 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[CH2:32][CH2:33][NH2:34].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[CH2:32][CH2:33][NH:34][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH2:21][CH3:22])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Reactant: NCCc1c(Cl)cccc1Cl
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2c(Cl)cccc2Cl)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(2,6-dichloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H27Cl2NO5 [M−H]−: 466, [M+H]−: 468.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:16]=2)=[CH:22][CH:21]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(O)cc2)on1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(OCc3ccccc3)cc2)on1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-hydroxyphenyl)isoxazole (0.2 g) was dissolved in dimethylformamide (2 ml), and 55% sodium hydride (oil, 0.03 g) was added thereto at 5° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture at the same temperature for 10 minutes. Then, benzyl bromide (0.08 ml) was added dropwise thereto and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain the title compound (0.14 g, 54%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:27]2[O:26][CH2:25][C:21]3([CH2:24][S:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:28][CH3:29])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:27]2[O:26][CH2:25][C:21]3([CH2:24][S:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:28][CH3:29])=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(CO2)CSC1
Reactant: Cc1c(Cl)cncc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CO2)CSC1

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (366 mg, 2.26 mmol) with compound 516 (516 mg, 1.74 mmol) in THF (10 mL) in the presence of LiHMDS (5.2 mL, 5.2 mmol) afforded compound 123 as a white solid material after purification by column chromatography (55-65% EtOAc in light petroleum). LC-MS: RT=4.23 min.; m/z 426.24, 428.25 (M+H)+, 424.23 (M−H)−. 1H NMR (CDCl3): δ 8.51 (2H, s), 7.57 (1H, d, J 9.2), 6.71 (1H, d, J 9.2), 4.64 (2H, s), 4.46 (2H, s), 4.33 (2H, s), 3.93 (3H, s), 3.20 (2H, d, J 9.9), 3.12 (2H, d, J 9.9).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH:40]([CH3:49])[C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:40]([CH3:49])[CH2:41][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(Cl)C(=O)N1CCCCC1
Product: CCN(Cc1ccc(OC(C)CN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 63.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-piperidin-1-ylpropan-1-one (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (14 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Br:9][CH:10]([CH3:14])[C:11](Cl)=[O:12]>ClCCl.O>[Br:9][CH:10]([CH3:14])[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: CC(Br)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Product: CC(Br)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloroaniline (400 mg, 3.13 mmol) in anhydrous dichloromethane at room temperature under N2 was added slowly 2-bromopropanoyl chloride (474 μL, 4.7 mmol). The reaction mixture was stirred at room temperature for 2 h and then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to give 2-bromo-N-(4-chlorophenyl)propanamide, which was used without further purifications.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=O.N1CCCC1>CO>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccccn1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2ccccc2C1=Cc1ccccn1
Yield: 84.4 %

Procedure:
A mixture of oxindole (37.5 g, 0.28 mole), pyridine2-carboxaldehyde (31.8 g, 0.29 mole) and pyrrolidine (21 ml) in 90 ml of methanol is heated on a steam bath. Within a short time an exothermic reaction occurs, resulting in the deposition of a thick solid mass. The solids are collected, washed with methanol and recrystallized from methanol to give 52.5 g of product: m.p. 204°-205°.
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([C:17](=[O:19])[CH3:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:20][Al](C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([C:17]([OH:19])([CH3:20])[CH3:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(=O)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Reactant: C[Al](C)C
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(O)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)ethanone (171 mg, 0.67 mmol) in CH2Cl2 (5.6 mL) was treated dropwise at 0° C. with trimethylaluminium (0.56 mL of a 2.0 M solution in toluene, 1.12 mmol) and the resulting yellow solution was stirred for 90 min at 0° C. Sat. aq. NH4Cl was added to the reaction mixture which was extracted with CH2Cl2 (3×25 mL) and the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.88 min, [M+H]+=272.20.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:11][C:12]1[CH:17]=[C:16]([C:6]2[C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=[CH:8][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1c(F)cccc1I
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1c(F)cccc1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 32.1 %

Procedure:
In a dry round bottom flask were added 2-fluoro-6-iodobenzonitrile (500 mg; 2.02 mmol), 3-chlorophenyl boronic acid (380 mg; 2.43 mmol), sodium carbonate (2.32 g; 21.86 mmol), tetrakis(triphenylphosphine)palladium(0) (77 mg; 0.07 mmol), DME (20 mL) and water (20 mL) and heated to reflux for 8 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×), washed with brine (1×) and water (1×). Organic layers were combined and dried over sodium sulfate and then filtered and solvent removed to yield crude material which was purified by column chromatography (4% ethyl acetate/hexane) to obtain 150 milligrams of 3′-chloro-3-fluorobiphenyl-2-carbonitrile.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=2)[C:16]([C:27](OCC)=[O:28])=[C:15]1[CH:32]([CH3:34])[CH3:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N1C2C(=CC(OCOC)=CC=2)C(C(O)=O)=C1C(C)C)C1C=CC=CC=1>C1COCC1>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=2)[C:16]([CH2:27][OH:28])=[C:15]1[CH:32]([CH3:34])[CH3:33])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(OCOC)cc12
Agent: COCOc1ccc2c(c1)c(C(=O)O)c(C(C)C)n2Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COCOc1ccc2c(c1)c(CO)c(C(C)C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of lithium aluminum hydride (LiAlH4, 144 mg, 3.6 mmol) in THF (10 ml) at 0° C. was added 1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indole-3-carboxylic acid, ethyl ester (Compound 2, 270 mg, 0.71 mmol) in THF (5 ml) slowly. The reaction was stirred at room temperature for 4.5 h, cooled to 0° C., and it was quenched with H2O (0.7 ml) and 4 M NaOH (1.0 ml), Silica gel was added, and the mixture was diluted with EtOAc, and filtered through Celite, and it was concentrated to yield the crude product, (1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indol-3-yl)methanol (Compound 3) as a clear oil, which was used immediately in the next step (Example 4) without further purification or characterization.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1)([O-:3])=[O:2].[CH:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:20]1([C:23]([N:17]2[CH2:16][CH2:15][N:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=3)[CH2:19][CH2:18]2)=[O:24])[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cnc(N2CCNCC2)c2ccccc12
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(C1CC1)N1CCN(c2ncc([N+](=O)[O-])c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Treat a solution or slurry of 4-nitro-1-piperazin-1-yl-isoquinoline (Preparation 26, 517 mg, 2 mmol), cyclopropanecarboxylic acid (258 mg, 3 mmol) and catalytic DMAP (24 mg, 0.2 mmol) in dichloromethane (20 mL) with EDCI (575 mg, 3 mmol). Agitate the resulting mixture at ambient temperature overnight, then wash with saturated aqueous sodium bicarbonate solution. Dry the organic layer over sodium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography using a gradient of 0-2% 2M ammonia-methanol in dichloromethane and a gradient of 0-70% ethyl acetate in hexanes to give a yellow solid after two purifications. (513 mg, 79% yield, LCMS ES+ (m/z) 327 [M+H]).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[O:7].[Cl:15][C:16]1[CH:31]=[C:30]([Sn:32]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:28][C:17]=1[C:18](ON1C(=O)CCC1=O)=[O:19]>CN(C)C=O>[Cl:15][C:16]1[CH:31]=[C:30]([Sn:32]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:28][C:17]=1[C:18]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][NH:8][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7])=[O:19]
Reactant: N[C@@H](CNC(=O)c1cccs1)C(=O)O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)ON2C(=O)CCC2=O)c(Cl)c1
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Reaction time: 72 h

Procedure:
A mixture of 3-(thiophene-2-carbonyl)amino-L-alanine on Wang resin (2.00 g) and 1-[[2-chloro-4-(tributylstannyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 374; 2.50 g, 4.6 mmol) in N,N-dimethylformamide was shaken for 72 h. The resin was washed with dichloromethane and methanol to give N-[2-chloro-4-(tri-n-butylstannyl)benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine on Wang resin.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[O:8][CH2:7]1)[CH:2]=[CH2:3].[CH2:9]([NH2:12])[CH2:10][CH3:11]>C(O)C>[CH2:1]([O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:12][CH2:9][CH2:10][CH3:11])[CH:2]=[CH2:3]
Reactant: CCCN
Reactant: C=CCOCC1CO1
Solvent: CCO
Product: C=CCOCC(O)CNCCC

Procedure:
Allylglycidyl ether (94.7 g.) is added with stirring to a solution of n-propylamine (98 g., 137 ml.) in ethanol (200 ml.). The mixture is heated under reflux for 18 hours and the solvent in excess of n-propylamine are distilled off. The residual oil is distilled and the fraction b.p. 79°-85° C. at 1 m.m. is collected to give 1-allyloxy-3-n-propylamino-2-propanol.