Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=O.C=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>C(#N)CC>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: C=Cc1ccccc1
Reactant: O=C(Cl)c1cccc(I)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Ic1cccc(C=Cc2ccccc2)c1
Yield: 10 %

Procedure:
The procedure described in Example 1 is followed, except that 26.65 g (0.1 mol) of 3-iodobenzoyl chloride, 13 g (0.125 mol) of styrene, 12.93 g (0.1 mol) of ethyl-diisopropylamine and 0.575 g (0.001 mol) of bis-(dibenzylidene-acetone)-palladium(O) are used. After a reaction time of 3 hours at the reflux temperature in 150 ml of propionitrile, 3.05 g (0.01 mol) of 3-iodostilbene, corresponding to a yield of 10% of theory, are obtained; melting point 96° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH2:22]([O:24][C:25](=[O:32])[C@:26]([F:31])([CH3:30])[C:27](O)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:32])[C@:26]([F:31])([CH3:30])[C:27]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:28])[CH3:23]
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)[C@@](C)(F)C(=O)O
Product: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(CCOC)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and (S)-2-fluoro-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (50%). MS: m/e=429(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[CH:4][CH:3]=1.[CH:18]1([CH2:21][NH2:22])[CH2:20][CH2:19]1.[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:22][CH2:21][CH:18]2[CH2:20][CH2:19]2)=[CH:4][CH:3]=1
Reactant: NCC1CC1
Reactant: O=Cc1cccc(OCc2ccc(Cl)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Clc1ccc(COc2cccc(CNCC3CC3)c2)cc1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
A solution of 62 g of 3-(4-chlorobenzyloxy)-benzaldehyde and 20 g of cyclopropylmethylamine in 750 ml of methanol was stirred at room temperature for 15 minutes. Thereto was slowly added 12 g of sodium borohydride with ice-cooling. The resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was dissolved in 1 liter of chloroform. The solution was washed with water, dried with anhydrous magnesium sulfate, and subjected to vacuum distillation to remove the solvent, whereby 81 g of 3-(4-chlorobenzyloxy)-N-cyclopropylmethylbenzylamine was obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[CH:11]=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[N:23]1[O:24][C:25]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)=[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=12>>[N:23]1[O:24][C:25]([NH:32][C:33]([N:15]2[CH2:14][CH2:13][C:12](=[CH:11][C:10]3[CH:18]=[CH:19][CH:20]=[C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:22][CH:21]=4)[CH:9]=3)[CH2:17][CH2:16]2)=[O:34])=[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=12
Reactant: Fc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Reactant: O=C(Nc1onc2ccccc12)Oc1ccccc1
Agent: Cl
Product: O=C(Nc1onc2ccccc12)N1CCC(=Cc2cccc(Oc3ccc(F)cc3)c2)CC1
Yield: 99.2 %

Procedure:
Following the procedure in Example 1, Step 6, 4-[3-(4-fluoro-phenoxy)-benzylidene]-piperidine hydrochloride (200 mg, 0.625 mmol) (Step 3) and phenyl benzo[c]isoxazol-3-ylcarbamate (175 mg, 0.688 mmol) were used to provide the title compound (275 mg). MS (APCI 10V) AP+ 444.2, 284.2, AP− 442.2; 1H NMR (400 MHz, CDCl3) δ ppm 2.46-2.52 (m, 2H) 2.57-2.63 (m, 2H) 3.56-3.62 (m, 2H) 3.66-3.72 (m, 2H) 6.39 (s, 1H) 6.78-6.87 (m, 2H) 6.91-6.96 (m, J=7.93, 1.25, 0.68, 0.57 Hz, 1H) 6.97-7.07 (m, 4H) 7.25-7.31 (m, 2H) 7.47 (dt, J=8.41, 0.77 Hz, 1H) 7.50-7.55 (m, 1H) 7.71 (s, 1H) 8.09 (d, J=7.90 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][C:11]2(OCC[O:15]2)[C:10]1([CH3:26])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.S(=O)(=O)(O)O>O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]1([CH3:26])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][OH:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CO)CCCC1(C)C(OCc2ccccc2)CCCC12OCCO2
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(CO)CCCC1(C)C(=O)CCCC1OCc1ccccc1
Yield: 99.8 %

Procedure:
A mixture of (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexane (13.9 g, 0.0384 mol), acetone (150 ml), water (20 ml) and 0.002 N sulfuric acid (50 ml) is refluxed for 18 hours under a nitrogen atmosphere. The reaction mixture is cooled, the acetone evaporated under reduced pressure and the aqueous layer extracted with ether (3×500 ml). The combined organic layers are washed with saturated sodium bicarbonate (100 ml), saturated sodium chloride (2×200 ml) and dried (MgSO4). The solvents are removed to afford (2S*, 3R*)-3-benzyloxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexanone (crude product, 12.2 g, 100%): ir (neat) 3484 (OH), 1709 cm-1 (CO); nmr (CDCl3)δ 0.88 (d, J=6 Hz, 3H, --CH--CH3), 1.08 (s, 3H, CH3), 3.42 (m, 4H, HO--CH2 --CH--, OH and --CH--O--CH2Ph), 4.50 (d of d, J=10 Hz, 2H, Ph--CH2 --O--), 7.2 (s, 5H, aromatic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][C:12]([CH3:14])=[C:11]([C:15]([OH:17])=O)[CH:10]=1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([CH2:24][N:25]([CH3:27])[NH2:26])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([CH2:24][N:25]([CH3:27])[NH:26][C:15]([C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[O:13][C:12]=2[CH3:14])=[O:17])=[CH:22][CH:21]=1
Reactant: COc1ccc(CN(C)N)cc1
Reactant: COc1ccccc1-c1cc(C(=O)O)c(C)o1
Product: COc1ccc(CN(C)NC(=O)c2cc(-c3ccccc3OC)oc2C)cc1

Procedure:
5-(2-Methoxyphenyl)-2-methylfuran-3-carboxylic acid prepared in the Step 20-1-3 and N-(4-methoxybenzyl)-N-methylhydrazine prepared in the Step 14-1-2 were used and subjected to the same procedure as in Example 16-1 to give the title compound.
Reaction SMILES: [CH3:1][Mg]Cl.[S:4]1[CH:8]=[C:7]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[N:6]=[N:5]1>O1CCCC1>[S:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH:13]([OH:14])[CH3:1])=[CH:15][CH:16]=2)[N:6]=[N:5]1
Reactant: C[Mg]Cl
Reactant: O=Cc1ccc(-c2csnn2)cc1
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2csnn2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Methylmagnesium chloride (3 M in tetrahydrofuran) (0.83 mL, 2.5 mmol) was added to a −78° C. solution of 4-(1,2,3-thiadiazol-4-yl)benzaldehyde (473 mg, 2.5 mmol) in tetrahydrofuran (10 mL). After stirring at −78° C. for 2 h, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 1-[4-(1,2,3-thiadiazol-4-yl)phenyl]ethanol.
Reaction SMILES: [CH3:1][C:2](=[C:8]([CH3:12])[CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H][H]>C(OCC)(=O)C.[Pt]>[CH3:1][CH:2]([CH:8]([CH3:12])[CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)=C(C)C(C)C
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)C(C)C(C)C
Yield: 83 %

Procedure:
20.0 g (117 mmol) of a double-bond isomer mixture of ethyl 2,3,4-trimethylpent-2-enoate (synthesis: see example 1) were dissolved in 200 ml of ethyl acetate, treated with 0.50 g (0.26 mmol, 0.2 mol %) of 10 percent platinum on activated carbon, and hydrogenated at room temperature for 4 hours in an autoclave at a hydrogen atmosphere of 25 bar with vigorous stirring. The catalyst was separated off by filtering the reaction mixture with suction over Celite. After the solvent had been removed on a rotary evaporator, the mixture was distilled under reduced pressure over a 10 cm Widmer column, giving 16.9 g (83%) of colorless ethyl 2,3,4-trimethylvalerate at a boiling point of 105-108° C./100 mbar. These 16.9 g (98.1 mmol) were dissolved in 150 ml of ethanol/water (1:1) and 9.60 g (147 mmol) of 86 percent potassium hydroxide were added. The reaction mixture was refluxed for 2 hours and, after cooling, diluted with 500 ml of water and adjusted to pH 1 with hydrochloric acid. The aqueous phase was extracted three times with ether, and the combined organic phases were dried over sodium sulfate and evaporated on a rotary evaporator. This gave 14.3 g of crude 2,3,4-trimethylvaleric acid which was dissolved in 250 ml of dry tetrahydrofuran. At −10° C., 9.8 ml (98 mmol) of 10 M butyllithium solution in hexane were added dropwise. After the mixture had been stirred for 40 minutes at −10° C., 123 ml (98 mmol) of 0.8 M propenyllithium solution in ether were slowly added dropwise at this temperature. After stirring for 4 hours at 30° C., the mixture was cooled to −10° C., and 16 ml (218 mmol) of acetone were added dropwise at this temperature. After the mixture had been stirred for a further 10 minutes at −10° C., 200 ml of saturated ammonium chloride solution were added dropwise at this temperature. The cooling was removed and the reaction mixture was diluted with 200 ml of water. The aqueous phase was extracted three times with ether, and the combined organic extracts were dried over magnesium sulfate and evaporated on a rotary evaporator. Flash chromatography (pentane/ether, 19:1, Rf=0.24) over silica gel gave 6.50 g (39%) of (2E)-5,6,7-trimethyloct-2-en-4-one as a colorless liquid with a pleasant odor.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH:20]1([C:26]2[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:26]2[CH:27]=[CH:28][C:29]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=4[CH:19]=3)=[CH:30][CH:31]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ccc(C2CCCCC2)cc1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[NH:5][C:6]=1[CH2:7][CH2:8][CH3:9].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[N:30]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[N:5]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: CCCc1[nH]c(C=O)cc1Br
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCc1c(Br)cc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 75 %

Procedure:
This compound was prepared using the same procedure as in Example 1. 4.3 g of 4-bromo-5-n-propyl-2-pyrrolaldehyde (0.020 moles) and 11 g of 4′-bromomethyl-2-(1-triphenylmethyltetrazol-5-yl)biphenyl (0.020 moles) yield 10 g of product which are used in the subsequent step. Formula: C41H34BrN5O (m.w. 692.66). Yield 75%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][N:21]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[O:24][CH2:23][C:22]2=[O:33])[CH:14]([C:34]([O:36]C)=[O:35])[CH2:13]1.[OH-].[Na+].Cl>CO.O>[C:31]([C:28]1[CH:29]=[CH:30][C:25]2[O:24][CH2:23][C:22](=[O:33])[N:21]([CH2:20][CH2:19][CH2:18][CH:15]3[CH2:16][CH2:17][N:12]([CH2:11]/[CH:10]=[CH:9]/[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:13][CH:14]3[C:34]([OH:36])=[O:35])[C:26]=2[CH:27]=1)#[N:32]
Reactant: COC(=O)C1CN(C/C=C/c2cc(F)ccc2F)CCC1CCCN1C(=O)COc2ccc(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2c(c1)N(CCCC1CCN(C/C=C/c3cc(F)ccc3F)CC1C(=O)O)C(=O)CO2
Reaction time: 64 h

Procedure:
A solution of methyl 1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4H-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate (Example 64) (73 mg, 0.143 mmol) in methanol (12 mL) and water (5 mL) was treated with sodium hydroxide solution (1N, 1 mL). After 64 hours, the pH was adjusted to 6 with 1N HCl. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel using methanol in dichloromethane (0-10%) and trituration with diethyl ether gave the title compound as a colorless solid, mixture of diastereomers, 10 mg (14%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[CH2:3][CH2:4][C:5]#[N:6].C(N(C(C)C)CC)(C)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]([CH3:9])([CH2:7][O:8][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:3][CH2:4][C:5]#[N:6]
Reactant: CC(C)(CO)CCC#N
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CCC#N)CO[Si](C)(C)C(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of 16.13 g (0.127 mmol) of 4,4-dimethyl-5-hydroxyvaleronitrile in 250 mL of dry CH2Cl2 was added, at 20° C., in 2 min., 24.2 mL (0.139 mmol; 1.09 eq) of diisopropylethylamine, followed after 5 min. by 25.0 g (0.165 mmol; 1.3 eq) of solid t-butyldimethylsilyl chloride, all at once. Then, 1.55 g (0.0127 mmol; 0.1 eq) of 4-dimethylaminopyridine was added and the whole was stirred at 20° C. during 18h. After removing the solvent under vacuum (aspirator) the brown residue was taken up in H2O, followed by ethyl ether. The layers were separated and the aqueous one extracted three times with 200 mL of ether. The combined organic layers were back extracted with water (100 mL), HCl 1.2N (100 mL), 5% KHCO3 (2×100 mL), dried over Na2SO4 and concentrated under vacuum to give a faint yellow oil. Distillation at 94°-97° C. (0.7 mm) gave 21 g (69%) of the title compound. TLC: (Silica), Rf 0.59 (CH2Cl2), detection with molybdophosphoric acid blue on yellow.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[CH3:25][S:26]([C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32])(=[O:28])=[O:27]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:31]([C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[S:26]([CH3:25])(=[O:28])=[O:27])=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccccc1S(C)(=O)=O
Yield: 99 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(2-methylsulfonylphenyl)carbonyl]-L-phenylalanine methyl ester was prepared in 99% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-methylsulfonylbenzoic acid using the general procedure described in example, LR MS: 548 (M+).
Reaction SMILES: [OH:1][C@H:2]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:21]Br.O>CC(O)=O>[Br:21][C:18]1[S:17][C:16]([C@@H:2]([OH:1])[C@@H:3]2[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: BrBr
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1cccs1
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To 0° C. solution of (±)-(4R*,5R*)-5-((1S*)-hydroxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-one (9.76 g, 34 mmol) in AcOH (246 mL) was added bromine (2 mL 38.8 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 2 h, then poured into water (500 mL). The resulting mustard colored precipitate was isolated via filtration and washed with water to yield (±)-(4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenylpyrrolidin-2-one (6.47 g, 52%): mp 105° C.; TLC (EtOAc) Rf 0.48.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH2:37].[CH3:39][N:40]=[C:41]=[O:42]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:41]([NH:40][CH3:39])=[O:42]
Reactant: CN=C=O
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 52 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) and methyl isocyanate as the starting materials in 52% yield. LCMS for C19H19ClN7O (M+H)+: m/z=396.1. 1H NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 9.31 (s, 1H), 8.99 (m, 1H), 8.30 (m, 2H), 8.18 (s, 1H), 7.84 (m, 1H), 7.65 (d, 1H), 7.56 (d, 1H), 6.98 (dd, 1H), 6.40 (bs, 1H), 2.96 (m, 4H), 2.64 (d, 3H).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>CO.C(Cl)(Cl)Cl>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1
Yield: 62.8 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(4-methylphenyl)thiophene (100 mg, 0.37 mmol) with 5-amino-4-bromo-3-methylisoxazole (65 mg, 0.37 mmol) yielded, after column chromatography using 10% MeOH/CHCl3, 96 mg final product as a pale yellow solid, (63% yield, m.p. 175° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:7]=12.CN(C=O)C.Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ccc(O)c2c1OCC21CC1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c2c1OCC21CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol (Intermediate 13, 176 mg, 1 mmol) in dry DMF (4 ml) potassium carbonate (207 mg, 1.5 mmol) and then 2-chloro-5-nitropyridine (158 mg, 1 mmol) were added and the reaction mixture was stirred for 2 hours at 80° C. After cooling the reaction mixture was quenched with water (2 ml), diluted with brine (10 ml) and extracted with ethyl acetate (2×20 ml). The organic layer was dried over sodium sulfate, filtered and evaporated affording the title compound (270 mg) as an orange solid that was used in the next step as crude material without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23](O)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:48][CH2:49][NH2:50]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([NH:50][CH2:49][CH2:48][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]([F:40])([F:51])[F:52])=[O:24])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1C(F)(F)F
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)NCCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The carboxylic acid from Example 156A (60 mg, 0.14 mmol) and HOBt (27.0 mg, 0.20 mmol) are placed in 0.86 ml DMF and treated at RT with 38.2 mg (0.20 mmol) of EDC. After 20 mins, 27 mg of 2-(2-trifluoromethyl-phenyl)ethylamine (0.14 mmol) are added and the mixture is stirred overnight at RT. The mixture is then directly separated by preparative HPLC (Method 20). 69 mg (91% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[C:6]([C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:19])[CH:3]=1.C[O:21]C(O)C>P(=O)(O)(O)O.O>[CH3:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][C:3]1=[O:21]
Reactant: Cn1cc(Cl)c2cccc(C(=O)c3ccccc3)c21
Reactant: COC(C)O
Agent: O=P(O)(O)O
Solvent: O
Product: CN1C(=O)Cc2cccc(C(=O)c3ccccc3)c21

Procedure:
A solution of 46 grams (0.17 mol) of 3-chloro-1-methyl-7-benzoylindole in 250 ml of methoxy-ethanol and 60 ml of 70% phosphoric acid was heated at reflux under a nitrogen atmosphere for 5 hours. The solution was then cooled and diluted with 1.5 liters of water. The organic materials were extracted with methylene chloride and concentrated. The concentrated extract was chromatographed on silica gel and the product eluted with isopropyl ether. The residue obtained crystallized upon standing and was recrystallized from isopropyl alcohol to give 8.9 grams of 1-methyl-7-benzoylindolin-2-one, having a m.p. of 89°-90.5° C.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([NH:12][C:13]([CH3:32])([C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[C:19]([CH3:30])[CH:18]=2)[CH3:14])=[O:11])=[CH:7][CH:6]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[C:4]([C:5]1[S:9][C:8]([C:10]([NH:12][C:13]([CH3:32])([C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[C:19]([CH3:30])[CH:18]=2)[CH3:14])=[O:11])=[CH:7][CH:6]=1)#[CH:3]
Reactant: Cc1cc(NC(=O)C(C)(C)NC(=O)c2ccc(C#C[Si](C)(C)C)s2)ccc1N1CCOCC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: C#Cc1ccc(C(=O)NC(C)(C)C(=O)Nc2ccc(N3CCOCC3=O)c(C)c2)s1
Reaction time: 2 h

Procedure:
A mixture of 0.81 g (1.63 mmol) of 5-(2-trimethylsilylethynyl)-N-{1-methyl-1-[3-methyl-4-(3-oxomorpholin-4-yl)phenylcarbamoyl]ethyl}thiophene-2-carboxamide and 0.57 g (1.79 mmol) of tetrabutylammonium fluoride trihydrate in 30 ml of methylene chloride is stirred for 2 h and then the organic phase is washed 3× with water, dried with sodium sulphate, filtered and concentrated in vac. The crude product is purified by chromatography (silica gel, methylene chloride→methylene chloride:ethanol 25:1).