Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1.C(N(CC)CC)C>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:12]1[CH:13]=[C:14]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=2)[C:8]#[N:9])[CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1cncc(C#N)c1
Reactant: Fc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2cccc(F)c2)c1
Temperature: 80 °C
Yield: 73 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (390 mg, 0.56 mmol), copper (I) iodide (211 mg, 1.11 mmol), and 5-ethynylnicotinonitrile (1.50 g, 11.7 mmol), (prepared essentially as described in PREPARATION 4), to a solution of 1-fluoro-3-iodobenzene (1.31 mL, 11.1 mmol) in triethylamine (21.6 mL, 155 mmol) and heat to 80° C. in a sealed tube for 1.5 h. Cool to room temperature and dilute with ethyl acetate. Wash with a 50% saturated aqueous solution of sodium bicarbonate. Back-extract the aqueous layer three times with dichloromethane and twice with ethyl acetate until the aqueous layer is no longer an emulsion. Combine all organic layers and wash with a saturated aqueous solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Dissolve the residue in ethyl acetate and filter through diatomaceous earth then purify by silica gel chromatography, eluting with a gradient from 95:5 to 80:20 (90:10 hexanes:ethyl acetate):dichloromethane. Further purify by silica gel chromatography, eluting with dichloromethane then 95:5 dichloromethane:ethyl acetate, to give the title compound as a white crystalline solid (1.8 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[N+:17]([O-])=O)[CH:5]=[C:6]([F:8])[CH:7]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([NH2:17])=[CH:12][CH:13]=[C:14]([F:16])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1cc(F)cc(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (3,5-difluorophenyl)-(5-fluoro-2-nitrophenyl)amine (2.0 g, 7.5 mmol) in EtOAc (65 mL) was added to a slurry of palladium on carbon (10% by wt, 200 mg) in EtOAc (10 mL) under nitrogen. The reaction mixture was stirred at RT under an atmosphere of hydrogen for 4 h. The mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PPC, gradient 0-30% EtOAc/cyclohexane) to afford the title compound as a white solid that turned red upon standing (1.07 g, 60%). LCMS (Method C): RT 3.40 min [M+H]+ 239. 1H NMR (CDCl3, 400 MHz): δ 6.90-6.87 (1H, m), 6.81-6.73 (2H, m), 6.31-6.23 (3H, m), 5.42 (1H, bs), 3.58 (2H, bs).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:29])[NH:21][CH2:22][CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:17]=[CH:16][C:15]=3[F:30])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:31][N:32]([CH3:52])[CH2:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[C:25]([O:24][CH2:23][CH2:22][NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]([F:30])=[C:14]([NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:40]4[CH:39]=[N:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:31])[CH3:52])=[CH:42][CH:41]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[CH:19]=1)=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OCCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: CN(C)CCCOc1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCCOC(C)(C)C)ccc4F)cnc3c2)cn1

Procedure:
7-Bromo-N-(5-(2-tert-butoxyethylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (Intermediate 2A) (300 mg, 0.629 mmol), N,N-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)propan-1-amine (202 mg, 0.660 mmol) and cesium carbonate (819 mg, 2.51 mmol) were combined in 1,2-dimethoxyethane (7 ml) and water (3 ml). The mixture was degassed thoroughly refilling with nitrogen and treated with PdCl2(dppf).CH2Cl2 adduct (25.7 mg, 0.031 mmol). The mixture was once again degassed thoroughly refilling with nitrogen and heated using microwave radiation at 100° C. for 1 hr. The aqueous was removed by pipette and the organic portion was absorbed onto silica and purified by chromatography eluting with 0-20% MeOH in DCM. The resulting solid was recrystallised from EtOAc to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[CH2:30])[CH2:10][CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([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)[CH:5]=[CH:6][C:7]=1[Cl:8].[N+](=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34]([O:36][CH3:37])=[O:35])=[N-].C([O-])(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:10][CH2:11][O:12][Si:13]([C:26]([CH3:27])([CH3:29])[CH3:28])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:30][C:33]2([C:38]([O:40][CH3:41])=[O:39])[C:34]([O:36][CH3:37])=[O:35])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Reactant: C=C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)C1(C(=O)OC)CC1(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 82.3 %

Procedure:
{[3-(3,4-Dichlorophenyl)-3-buten-1-yl]oxy}(1,1-dimethylethyl)diphenylsilane (P13, 2.25 g), dimethyl diazopropanedioate (1.2 g) (prepared in an analogous manner as reported in Synthetic Communications, 17(4), 1709-16, 1987) and rodhium (II) acetate dimer (0.060 g) were mixed together and heated at 100° C. for 40 min. After cooling, the residue was treated with DCM and the mixture was filtered. The filtrate was evaporated under reduced pressure and the crude product was purified by flash chromatography (Cy/EA from 1/0 to 95/5) to give the title compound (2.38 g) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C:16](=[O:18])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH3:19][Mg]Br>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[F:9][C:6]1[CH:5]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C:16]([OH:18])([CH3:19])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:3]=[C:2]([F:1])[C:7]=1[F:8]
Reactant: C[Mg]Br
Reactant: CC(=O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1

Procedure:
To a solution of 1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethanone (529 mg) in tetrahydrofuran (25 mL) was, under a nitrogen atmosphere, dropwise added methylmagnesium bromide (0.97 M tetrahydrofuran solution, 4.63 mL) at 0° C. The resultant solution was stirred for 1 hour at the same temperature, and then diluted with aqueous ammonium chloride and ethyl acetate. The organic layer was partitioned, washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate), to thereby obtain the titled compound (330 mg). The physical properties of this crude product were as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:31])[C:26]([O:28]CC)=O)[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:32][NH2:33]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:31])[C:26]([NH:32][NH2:33])=[O:28])[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)CC(C)C(=O)OCC
Reactant: NN
Solvent: CO
Product: CCOC(=O)C(C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
To a solution of (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (637 mg, 1.43 mmol) in MeOH (40 mL) is added a solution of 50% wt hydrazine (0.09 mL, 1.43 mmol) in MeOH (10 mL) at −20° C. After stirring for 18 hour at room temperature, the reaction mixture is concentrated under reduced pressure to give (45)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate (542 mg). HPLC retention time=1.54 minutes (condition A); MS 432.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]2[C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][C:31]=2[F:32])[NH:28][N:27]=[CH:26]3)=[O:21])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[CH2:33]([S:35]([NH:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]2[C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][C:31]=2[F:32])[NH:28][N:27]=[CH:26]3)=[O:21])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9])(=[O:37])=[O:36])[CH3:34]
Reactant: CCS(=O)(=O)Cl
Reactant: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(C(F)(F)F)c(N)c2)CC(=O)N1
Product: CCS(=O)(=O)Nc1cc(C2CC(=O)NC(C)=C2C(=O)Nc2cc3cn[nH]c3cc2F)ccc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in Example 78, beginning with the product from Example 80 and using ethanesulfonyl chloride in place of methanesulfonyl chloride. MS (ES+) m/e 414 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9])[CH3:2].Br[CH:52]([CH3:62])[C:53]([NH:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:54].C([O-])([O-])=O.[K+].[K+].N#N>CN(C=O)C>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:62][CH2:52][C:53]([NH:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:54])=[O:9])[CH3:2]
Reactant: CC(Br)C(=O)Nc1ccccc1
Reactant: CCCc1nc(CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc(CC)c(C(=O)OCCC(=O)Nc2ccccc2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.3 %

Procedure:
To a solution/suspension of 0.66 g 4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, 0.23 g 2-bromo-N-phenylpropionamide, and 0.15 g K2CO3 in 7 mL of DMF was added 0.17 g of KI. The reaction was stirred 10 minutes at room temperature, then heated in a N2 atmosphere at 70° C. overnight. The reaction was partitioned between H2O and EtOAc, and the organic extract washed with brine and dried with MgSO4. Filtration, concentration, and flash chromatography with a 10-60% EtOAc/hexanes gradient provided 0.35 g of pure product.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([O-:6])=[O:5].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(O)=O.[Rh]>[C:21]([NH:1][CH:2]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:3][C:4]([OH:6])=[O:5])([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(CC(=O)[O-])c1ccccc1
Agent: [Rh]
Solvent: CC(=O)O
Product: O=C(O)CC(NC(=O)OCc1ccccc1)C1CCCCC1
Reaction time: 30 h
Yield: 50.7 %

Procedure:
A solution of 25 g (151 mmol) of 3-amino-3-phenylproprionate in 450 mL of HOAc was charged with 25 g of 5% Rh/Al2O3 and the mixture hyrogenated at 60 psi for 30 hr at 60° C. The reaction was filtered over celite and evaporated in vacuo to a dark oil. The presence of the desired product was confirmed by FD-MS (m/e 172, MH+, 100). The crude reduction product was treated with benzylchloroformate (25.67 g; 151 mmol) under basic conditions substantially according to the procedures of Example 1, A, to afford 23.4 g of N-Cbz-3-amino-3-cyclohexyl propionic acid as a grey solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:14](N)([NH2:17])(=[O:16])=[O:15].O>O1CCOCC1>[NH2:17][S:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Solvent: O
Product: NS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Yield: 65.5 %

Procedure:
A solution of 1-benzylpiperazine (5 g, 28.4 mmol) and sulphamide (2.77 g) in 1,4-dioxane (25 ml) was heated under reflux for 24 hours. The solution was cooled and poured into water (100 ml). The solid was filtered off, washed with toluene (100 ml) and dried under reduced pressure to give the title compound (4.75 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]([NH2:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[CH3:10][O:9][C:7](=[O:8])[CH2:6][CH:5]([NH:11][C:13](=[O:15])[CH3:14])[CH2:4][C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)CC(N)CC(=O)OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CC(CC(=O)OC)NC(C)=O

Procedure:
21.7 Parts of 3-aminoglutaric acid dimethyl ester is acetylated with 100 parts by volume acetic anhydride in 130 parts by volume pyridine to give N-acetyl-3-aminoglutaric acid dimethyl ester which has the following structural formula ##STR17##
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C@@H:16]([CH2:20][NH:21][C:22]([C:24]1[N:25]=[CH:26][C:27]2[C:32]([C:33]=1[OH:34])=[CH:31][CH:30]=[C:29]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:28]=2)=[O:23])[C:17]([OH:19])=[O:18])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C@@H:16]([CH2:20][NH:21][C:22]([C:24]1[N:25]=[CH:26][C:27]2[C:32]([C:33]=1[OH:34])=[CH:31][CH:30]=[C:29]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:28]=2)=[O:23])[C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Yield: 75.2 %

Procedure:
TFA (0.4 mL) was added to a mixture of 2-(S)-tert-Butoxycarbonylamino-3-[(4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-propionic acid (99 mg, 0.21 mmol) in CH2Cl2 (2 mL). The resultant mixture was stirred at room temperature for 3 h and concentrated. Residue was taken up with water (100 mL) and the pH was adjusted by 1 N NaOH aq. Solution to 9-10, then acidified by 1 N HCl to pH=5. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 58 mg (0.158 mmol) in 75% yield. LC-MS ESI−: 366.10 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[OH:11])=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.O([Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[O:11][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1ccc(C(O)c2ccncc2)cc1-c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C(O[Si](C)(C)C(C)(C)C)c2ccncc2)cc1-c1ccccc1
Reaction time: 18 h
Yield: 93 %

Procedure:
4-(4-Pyridylhydroxymethyl)-2-phenylbenzoic acid methyl ester (769 mg, 2.41 mmol), prepared as in Example 297A, diisopropylethylamine (0.84 mL, 4.8 mmol), and t-butyldimethylsilyl triflate (1.1 mL, 4.8 mmol) were dissolved in methylene chloride (50 mL) and stirred for 18 hours. TLC indicated the presence of the alcohol so additional base (1 mL) and triflate (0.5 mL) were added. After 15 minutes, all starting alcohol was consumed. The reaction mixture was washed with water, 5% NaHCO3, and brine, dried over Na2SO4, and concentrated. Chromatography on silica gel (20% ethyl acetate-hexane) provided the desired compound in a 93% yield.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].C=O.O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:8][OH:9])[CH2:6][O:7][CH2:13][O:5][CH2:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(CO)(CO)CO
Agent: C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(CO)COCOC1
Reaction time: 3 h

Procedure:
In a one-liter three neck flask were placed 405 grams of 2-ethyl-2-hydroxymethyl-1,3-propanediol, 90 grams of paraformaldehyde, 0.9 grams of p-toluene sulfonic acid monohydrate and 150 ml of toluene. The flask was equipped with a Dean-stark trap and a condenser. The reaction mixture was stirred at a bath temperature of 120° C. to 170° C. for three hours. The toluene-water was collected, and after removing the toluene, the crude product was distilled under vacuum at 10-11 mm Hg and 115° C. to 117° C. 410 grams of 5-ethyl-5-hydroxymethyl-1,3-dioxane (EHMDO) were collected. The product was then dried by molecular sieve and had a water content of about 350 ppm. NMR spectra confirmed that EHMDO was obtained.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[C:5]([N+:24]([O-])=O)[CH:4]=1)#[N:2].O.NN>C(O)C.[Ni]>[NH2:24][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[C:8]([CH3:9])=[CH:7][C:6]=1[NH:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1C#N
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1C#N
Temperature: 45 °C
Yield: 85 %

Procedure:
A suspension of 1,1-dimethylethyl 4-[(4-cyano-5-methyl-2-nitrophenyl)amino]-1-piperidinecarboxylate (D91) (3 mmol) in ethanol (30 mL) was treated with Raney Nickel and hydrazine hydrate (30 mmol, 1.5 g, 10 eq) under argon at room temperature. The mixture was then heated at 45° C. for 1 h. The catalyst was then filtered off and washed with ethanol and methanol. The filtrate was concentrated under reduced pressure to give the title compound as a solid (2.55 mmol, 840 mg, 85% yield). M+H 331.3, 275.2, 231.2 (full molecule and fragments for loss of tert-butyl group and loss of Boc group).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:22]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][C:15]([F:14])([F:25])[F:26])=[CH:18][CH:19]=1)[CH2:11]2
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2c(I)cccc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.245 g, 0.7 mmol), 4-trifluoromethoxy-benzylamine (0.122 mL, 0.8 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.095 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.21 (s, 2H), 4.82 (s, 2H), 6.84 (d, 2H), 7.14-7.40 (m, 4H), 7.92 (d, 1H). GC-MS: m/z 433 (M)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:33])[O:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[C:15]1([NH:29][C:30](=[O:32])[CH3:31])[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:25]([O-])=O)[C:16]1=[O:28])[CH3:2].Cl>C(O)C.O.[Fe]>[CH2:1]([NH:3][C:4](=[O:33])[O:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[C:15]1([NH:29][C:30](=[O:32])[CH3:31])[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH2:25])[C:16]1=[O:28])[CH3:2]
Reactant: CCNC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCNC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2cccc(N)c2C1=O
Yield: 36 %

Procedure:
2-(2-acetamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethylcarbamate (0.27 g, 0.59 mmol) was dissolved in Ethanol (10 ml) and water (1 ml). This solution was added with iron (0.24 g, 4.3 mmol) and conc. HCl (0.03 ml). The reaction mixture was heated for 2 hrs under reflux. After filtrating and washing with MeOH, the remainder was concentrated in a vacuum and purified using column chromatography (ethylacetate:hexane=1:1) to afford the title compound (90 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[C@H:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([C@@H:31]5[CH2:35][CH2:34][CH2:33][C@H:32]5[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1O
Product: CCOC(=O)[C@@H]1CCC[C@H]1N1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
Ethyl (1R,2R)-2-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]cyclopentanecarboxylate was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and ethyl (1R,2S)-2-hydroxycyclopentanecarboxylate following General Procedure J.
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[C:9]=2[CH:23]=1)(O)=[O:3].[NH3:24]>CN(C)C=O.C(Cl)Cl.O>[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[C:9]=2[CH:23]=1)(=[O:3])[NH2:24]
Reactant: N
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccc(Cl)cc1Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2ccc(C(N)=O)cc2n1Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Oxylyl chloride (0.437 g) is added to a methylene chloride (8 ml) solution of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.490 g) and N,N-dimethylformamide (1 drop) under ice-chilled conditions, and the solution is stirred for 1.5 hours at room temperature. Then, 28% aqueous ammonia (4 ml) is added and the solution is stirred for 12 hours at room temperature. Water and methylene chloride are added to the reaction solution for extraction. After the organic layer is concentrated, precipitated crystals are collected, dried and 6-carbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.240 g) is obtained. 1H-NMR (DMSO-d6, δ): 2.48 (3H, s), 5.54 (2H, s), 6.41 (1H, d, J=8.4 Hz), 7.21-8.02 (3H, m), 7.31 (1H, dd, J=2.2 and 8.4 Hz), 7.60 (1H, d, J=8.4 Hz), 7.75 (1H, m), 7.93 (1H, s).