Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:12](Cl)(=[O:16])[O:13][CH2:14][Cl:15].C(OCC)C>ClCCl>[C:12](=[O:16])([O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)[O:13][CH2:14][Cl:15]
Reactant: OCC1CC1
Reactant: O=C(Cl)OCCl
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCl)OCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a solution of cyclopropylmethanol (0.39 ml, 5.0 mmol) and pyridine (0.40 ml, 5.0 mmol) in dichloromethane (4 ml), at 0° C. and under nitrogen, was added dropwise chloromethyl chlorocarbonate (0.40 ml, 4.5 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. To the mixture was added diethyl ether (15 ml) and the solid material was collected by filtration and washed with diethyl ether (10 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the title compound (725 mg) which was used directly.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].[I:9][C:10](=[C:23]([I:25])[I:24])[CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>CN(C)C=O>[I:9][C:10](=[C:23]([I:25])[I:24])[CH2:11][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]1
Reactant: O=[N+]([O-])c1cc[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(CC(I)=C(I)I)c1
Reaction time: 0.25 h

Procedure:
To a solution of 112 mg (1 mmole) of 3-nitropyrrole in 5.0 ml of dry N,N-dimethylformamide were added 606 mg of 2,3,3-triiodoallyl-p-toluenesulfonate and 60 mg (1.5 mmoles) of powdery sodium hydroxide and the reaction was carried out with stirring for 15 minutes.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Br[CH2:17][CH3:18]>CN(C)C=O>[CH2:17]([N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=[C:2]1[CH3:1])[CH3:18]
Reactant: Cc1nc2cccc([N+](=O)[O-])c2[nH]1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C)nc2c([N+](=O)[O-])cccc21
Temperature: 65 °C
Yield: 57 %

Procedure:
To a solution of 0.47 g (2.65 mmol) 2-methyl-4-nitrobenzimidazole, and 0.12 g (2.92 mmol) of sodium hydride in 10 mL of dry dimethylformamide was added 0.218 mL (2.92 mmol) bromoethane. The mixture was heated overnight at 65° C. The mixture was cooled to room temperature and the solvents were removed under reduced pressure. The resultant syrup was partitioned between water and ethyl acetate. The organic phase was evaporated to dryness and the syrup chromatographed on silica to yield 0.31 g (1.51 mmol, 52%) of a yellow syrup.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1[CH2:14][CH2:13][NH:12]C1=O>COCCOCCO>[ClH:1].[CH3:2][N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:14][CH2:13][NH2:12]
Reactant: CNc1ccccc1
Reactant: O=C1NCCO1
Agent: Cl
Solvent: COCCOCCO
Product: CN(CCN)c1ccccc1

Procedure:
In a procedure similar to Example 1, N-methylaniline hydrochloride (17.4 g, 0.10 mole), 2-oxazolidinone (8.7 g, 0.10 mole) and 50 ml of 2-(2-methoxyethoxy)-ethanol were heated for four hours. Removal of the solvent in vacuo gave a quantitative yield of N-methyl-N-phenyl-1,2-ethanediamine hydrochloride as a purplish solid. Workup as before afforded the crude diamine in also a quantitative crude yield as a dark yellow liquid. Distillation at 95° C. to 100° C. (0.5 mm Hg) gave a 79 percent yield of the purified product as a clear liquid. Spectral data and gas chromatographic analysis as compared to an authentic sample confirmed its structure.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](I)=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Br:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[CH3:18][C:19]([CH3:23])([CH3:22])[C:20]#[CH:21].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O1CCOCC1>[C:1]([NH:4][C:5]1[C:6]([C:21]#[C:20][C:19]([CH3:23])([CH3:22])[CH3:18])=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Br:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1cc(Br)c(NC(C)=O)c(I)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)c(NC(C)=O)c(C#CC(C)(C)C)c1O
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, methyl 4-acetylamino-5-bromo-3-iodosalicylate (I-250) (414 mg, 1.0 mmol), bis(triphenylphosphine)palladium(II) chloride (49 mg, 0.07 mmol), copper(I) iodide (19 mg, 0.1 mmol) and 3,3-dimethyl-1-butyne (0.13 ml, 1.1 mmol) were added to a mixed liquid of triethylamine (4 ml) and dioxane (6 ml), followed by stirring at 30° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, then saturated ammonium chloride water was added to the residue, followed by extraction twice with chloroform, the organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column, chromatography, and the eluate with n-hexane/ethyl acetate (2:1) gave the entitled compound (243 mg, 66.5) as a white solid.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:12](Cl)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CCOCC>[C:12]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)NCCCCCC(=O)O
Yield: 90.2 %

Procedure:
A one L beaker was charged with 250 mL of 1N sodium hydroxide solution (0.25 mol) and 32.8 g (0.25 mol) of 6-aminocaproic acid. The resulting solution was cooled in an ice bath and, with stirring, a solution of lauroyl chloride (54.7 g, 0.25 mol) in 100 mL ether was added dropwise while maintaining the pH of the stirred solution between 10 and 12 by addition of 10% sodium hydroxide solution. Addition of the lauroyl chloride required 45 min. During this period the reaction mixture became thick with solid and additional volumes of water and ether were added in order to keep the mixture stirrable. Following completion of the lauroyl chloride addition, the ice bath was removed and the mixture was stirred for 1.5 hr. at room temperature. The mixture was then adjusted to pH 2 with concentrated HCl, and the precipitate which formed was removed by filtration and washed with water. The resulting solid was slurried with hexane (200 ml), filtered, and washed 5 times with 100 ml portions of hexane. This hexane slurry/wash procedure was repeated a second time. The resulting solid was air dried to yield 70.7 g (90%) of N-lauroyl-6-aminocaproic acid, mp 87°-90° C. [lit mp 85°-86° C.--E. Jungerman, J. F. Gerecht, and I. J. Krems, J. Amer. Chem. Soc., 78, 172 (1956).]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:45][CH2:46][CH:47]4[CH2:48][CH2:49][N:50]([C:53]([O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[O:54])[CH2:51][CH2:52]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 13 h
Yield: 66 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(2-hydroxyethyl)piperidin-1-carboxylate (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, and being stirred for 13 h to provide the title compound (80 mg, 66%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:29]([CH:37]=O)[NH:28][C:27]=2[CH3:39])=[O:25])=[CH:19][CH:18]=1>>[N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:29]([CH:37]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[CH:4]4[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]4)[NH:11][C:10]3=[O:16])[NH:28][C:27]=2[CH3:39])=[O:25])=[CH:19][CH:18]=1
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)Nc1ccncc1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c(-c2ccccc2)c1C(=O)Nc1ccncc1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid pyridin-4-ylamide (67 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [CH:1](O)=[O:2].[NH2:4][C:5]1[C:6]2[C:31]([CH3:36])([C:32]([NH:34][NH2:35])=[O:33])[C:30](=[O:37])[NH:29][C:7]=2[N:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[N:12]=2)[N:10]=1>C(#N)C>[NH2:4][C:5]1[C:6]2[C:31]([CH3:36])([C:32]([NH:34][NH:35][CH:1]=[O:2])=[O:33])[C:30](=[O:37])[NH:29][C:7]=2[N:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:25])([F:24])[F:26])[N:12]=2)[N:10]=1
Reactant: O=CO
Reactant: CC1(C(=O)NN)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Solvent: CC#N
Product: CC1(C(=O)NNC=O)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 80 °C

Procedure:
Formic acid (3 mL, 78 mmol) was added to an acetonitrile solution (3 mL) of the intermediate from Step A (200 mg, 0.371 mmol). The reaction mixture was heated at 80° C. for 1.5 hours in a screw cap vial. The mixture was cooled, concentrated in vacuo and the residue diluted with EtOAc. The solution was then washed with saturated aqueous sodium bicarbonate, water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow solid which was used in the next step without further purification. m/z=513.97 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:6]([C:8]([F:11])([F:10])[F:9])=[CH2:7])C.C(OC(=O)C(C1C=CC(Cl)=CC=1)C(C(F)(F)F)C)C>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH:5]([CH:6]([C:8]([F:9])([F:10])[F:11])[CH3:7])[C:4]([OH:19])=[O:3])=[CH:17][CH:16]=1
Reactant: C=C(C(C(=O)OCC)c1ccc(Cl)cc1)C(F)(F)F
Agent: CCOC(=O)C(c1ccc(Cl)cc1)C(C)C(F)(F)F
Product: CC(C(C(=O)O)c1ccc(Cl)cc1)C(F)(F)F

Procedure:
Similarly, Ethyl-2-(4-chlorophenyl)-3-(trifluoromethyl)-but-3-enoate is hydrogenated to ethyl-2-(4-chlorophenyl)-3-(trifluoromethyl)-butanoate nD 1.4709.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]([SH:14])[CH2:9]1.Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1>CN(C=O)C.O>[CH3:7][C:8]1([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]([S:14][C:17]2[N:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)[CH2:9]1
Reactant: CC1(C)CCCC(S)C1
Reactant: N#Cc1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCCC(Sc2ccc(C#N)cn2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add potassium tert-butoxide (777 mg, 6.94 mmol) to a solution of 3,3-dimethylcyclohexanethiol (1 g, 6.94 mmol) in DMF (10 mL) and stir at room temperature for 10 min. Add 6-chloro-nicotinonitrile (547 mg, 3.96 mmol) and warm the solution to 60° C. for 18 h. Cool the mixture, dilute with water (100 mL) and extract with EtOAc (50 mL). Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate as a clear oil that solidifies on standing to a white solid (0.37 g, 38%).
Reaction SMILES: C([NH:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([CH3:18])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1)(=O)C.[ClH:19]>>[ClH:19].[NH2:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([CH3:18])[CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(C)c1ccc(NC(C)=O)nc1
Agent: Cl
Product: CC(CC(=O)O)c1ccc(N)nc1

Procedure:
A solution of (RS) ethyl 3-(6-acetylamino-pyrid-3-yl)-butanoate (25.56 g, Reference Example 21) in aqueous hydrochloric acid (500 mL, 6M) was heated at 100° C. for 3.5 hours, then cooled and then evaporated to give the title compound as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:18][C@@H:19]([O:35][C:36]([N:38]2[CH2:43][CH2:42][CH:41]([N:44]3[CH2:50][CH2:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=4[NH:46][C:45]3=[O:55])[CH2:40][CH2:39]2)=[O:37])[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)=[O:21])[CH:5]=[C:6]2[C:10]=1[N:9](C(OC(C)(C)C)=O)[N:8]=[CH:7]2.C([O-])([O-])=O.[K+].[K+]>Cl>[O:55]=[C:45]1[N:44]([CH:41]2[CH2:42][CH2:43][N:38]([C:36]([O:35][C@H:19]([CH2:18][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:20]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)[CH2:24][CH2:23]3)=[O:21])=[O:37])[CH2:39][CH2:40]2)[CH2:50][CH2:49][C:48]2[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=2[NH:46]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc2cnn(C(=O)OC(C)(C)C)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc2cn[nH]c12
Temperature: 50 °C

Procedure:
A solution of 160 mg (0.21 mmol) tert.-butyl 7-methyl-5-{(R)-3-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-3-oxo-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propyl}-indazol-1-carboxylate in 10 mL 1 M HCl was stirred for 1 h at RT. To complete the reaction the mixture was heated to 50° C. for 10 min and stirred for a further hour at RT. The mixture was combined with 15% K2CO3 solution, extracted three times with in each case 30 mL DCM and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was triturated with 30 mL diisopropylether, suction filtered, washed with 10 mL diisopropylether again and dried in the air.
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)=O.[Br-].[CH2:27]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(C)([O-])C.[K+]>>[C:28]1([CH:27]=[CH:1][C:3]2[C:8](=[O:9])[C:7]3[CH:10]=[C:11]([O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:12]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:6]=3[O:5][CH:4]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CS(=O)(=O)Nc1cc2occ(C=O)c(=O)c2cc1Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Product: CS(=O)(=O)Nc1cc2occ(C=Cc3ccccc3)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Formyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with benzyltriphenylphosphonium bromide in the presence of potassium tertbutoxide to obtain 3-(2-phenylvinyl)-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[C:8]=2[CH2:16][CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]1([C:7]2[N:11]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[C:8]=2[CH2:16][CH2:17][CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCc1c(C(=O)OC)c[nH]c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCCc1c(C(=O)OC)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Yield: 86.6 %

Procedure:
Using methyl 5-phenyl-4-propyl-1H-pyrrole-3-carboxylate (2.0 g), sodium hydride (60% in oil, 434 mg) and benzenesulfonyl chloride (1.60 g), a procedure as in Reference Example 4 was performed to give the title compound as colorless crystals (yield 2.73 g, 69%).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C@@H:13](Br)[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=O)C>CS(C)=O>[CH2:26]1[CH2:25][O:24][C:14]2([CH:13]=[CH:12][C@H:11]3[C@H:10]4[C@H:19]([CH2:18][CH2:17][C@:15]23[CH3:16])[C@:20]2([CH3:23])[C:7]([CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21]2)=[CH:8][CH2:9]4)[O:27]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3C[C@@H](Br)C23OCCO3)C1
Solvent: CS(C)=O
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=CC21OCCO1
Temperature: 45 °C
Reaction time: 22 h

Procedure:
16α-Bromo-17,17-ethylenedioxy-androst-5-en-3β-ol 3-acetate from Example 28A (50.000 g, 110.28 mmol) is dissolved in dimethyl sulfoxide (DMSO; 500 mL) and the solution is warmed to 45° C. under an inert atmosphere. After 22 hours, the reaction is partitioned between ether (2000 mL) and water (750 mL). The layers are separated and the ether solution is washed with brine (2×500 mL), dried over MgSO4, filtered and evaporated to dryness. The residue is recrystallized from ethanol-water to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:8][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]2)[C:11]=1[C:12]#[N:13]
Reactant: OCC1CCCNC1
Reactant: N#Cc1c(N)cccc1F
Product: N#Cc1c(N)cccc1OCC1CCCNC1

Procedure:
Prepared as in Example 24d from 3-piperidinemethanol and 2-amino-6-fluoro-benzonitrile as a light yellow solid (27%). MS 232 (MH+).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[N:39]1[C:47]2[C:42](=[CH:43][C:44]([NH2:48])=[CH:45][CH:46]=2)[CH:41]=[N:40]1.C(NC1C(C)=CC(C(OC)=O)=C(C)C=1)(=O)C.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(OCC)C.C1(C)C=CC=CC=1>[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[N:39]1[C:47]2[C:42](=[CH:43][C:44]([NH:48][C:2]3[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=3)=[CH:45][CH:46]=2)[CH:41]=[N:40]1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: Nc1ccc2c(cnn2C2CCCCO2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: COC(=O)c1cc(C)c(NC(C)=O)cc1C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1ccc(Nc2ccc3c(cnn3C3CCCCO3)c2)cc1
Reaction time: 8 h
Yield: 55.4 %

Procedure:
In a two-necked flask the inner atmosphere of which had been replaced with nitrogen were placed tert-butyl 4-bromobenzoate (2.57 mg, 1.00 mmol), toluene (2 ml), 18-crown-6 (380 mg, 1.40 mmol), the 1-(2-tetrahydropyranyl)-1H-indazol-5-amine (261 mg, 1.23 mmol) obtained in Example 317, (e) and sodium tert-butoxide (135 mg, 1.40 mmol) in that order. After the inner atmosphere of the flask was replaced with nitrogen again, tris(dibenzylideneacetone)(chloroform) dipalladium(0) (52 mg, 0.050 mmol) and (S)-2,2′-bis(diphenylphophino)-1,1′-binaphthyl (94 mg, 0.151 mmol) were added. After the third replacement of the inner atmosphere of the flask with nitrogen, stirring was conducted at 80° C. for 8 hours. The resulting mixture was diluted with diethyl ether and the solid was removed by filtration using Celite. Then, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain tert-butyl 4-{1-(2-tetrahydropyranyl)-1H-indazol-5-ylamino}benzoate (218 mg, 56%).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][N:31]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>>[CH3:8][C:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][N:18]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][N:31]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)=[CH:14][CH:15]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc([N+](=O)[O-])cn2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc([N+](=O)[O-])cn2)cc1)C(=O)O
Yield: 48.8 %

Procedure:
Ethyl 2-methyl-2-[4-(2-{(5-nitropyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (80 mg) was hydrolyzed with NaOH as per general procedure H. Purification by radial chromatography (1–5% methanol-dichloromethane gradient) followed by crystallization from dichloromethane-hexane afforded the title compound as a white solid (37 mg; 49% yield).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]([CH:20]([CH3:24])[C:21](Cl)=[O:22])=[CH:12][C:11]=1[C:25]([CH3:28])([CH3:27])[CH3:26]>CCCCCCC>[CH2:1]([NH:8][C:21](=[O:22])[CH:20]([C:13]1[CH:14]=[C:15]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:10]([OH:9])=[C:11]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:12]=1)[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C(=O)Cl)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCCCCCC
Product: CC(C(=O)NCc1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
To a solution of 22.4 g of benzyl amine (0.21 mol) in 100 ml of heptane 29.6 g of 4-hydroxy-3,5-di-tert.-butylphenyl-propionic acid-chloride (0.1 mol) -- dissolved in 200 ml of heptane -- were added dropwise at 20°C, then the solution was boiled under reflux for 3 hours. Working up followed in the manner described in Example 12.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:43]1([NH2:46])[CH2:45][CH2:44]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:46][CH:43]3[CH2:45][CH2:44]3)=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NC4CC4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and cyclopropanamine