Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:15][CH:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[N:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:17]1=[O:32]>CS(C)=O>[NH2:15][C:16]1([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:24]2[C:19](=[CH:20][C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[N:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:17]1=[O:32]
Reactant: C=CC(=O)OCC
Reactant: CCCCCN1C(=O)C(N)c2ccc(OC)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCN1C(=O)C(N)(CCC(=O)OCC)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, 0.85 ml of ethyl acrylate and 1.94 g of potassium carbonate were added to 2.00 g of 3-amino-2,3-dihydro-6-methoxy-2-oxo-1-pentyl-1H-indole hydrochloride dissolved in 40 ml of dimethyl sulfoxide, the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed and dried. Insolubles were removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography [chloroform-ethyl acetate (1:1)] to afford 1.36 g of ethyl 3-[3-amino-2,3-dihydro-6-methoxy-2-oxo-1-pentyl-1H-indol-3-yl]-propionate as a pale yellow oily product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[CH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:14]=[C:15]([CH:18]=[O:19])[S:16][CH:17]=1>O1CCCC1.[Cu]I.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.C(N(CC)CC)C>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:13]2[CH:14]=[C:15]([CH:18]=[O:19])[S:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: C#CCCCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1cc(C#CCCCc2ccccc2)cs1
Temperature: 50 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
5-Phenylpent-1-yne (18.1 g, 126 mmol) was dissolved in tetrahydrofuran (100 ml), and then 4-bromothiophen-2-carboxaldehyde (18.7 g, 98 mmol) in tetrahydrofuran (200 ml), triethylamine (150 ml, 1.07 mmol), copper(I) iodide (962 mg, 5.05 mmol), and dichlorobis(triphenylphosphine)palladium (3.54 g, 5.04 mmol) were added thereto, and the mixture was stirred at 50° C. for 4 hours under a nitrogen atmosphere. After the reaction solution was filtered, the filtrate was evaporated under reduced pressure. To the residue was added ether, and the solution was washed with water and a saturated aqueous sodium chloride solution, respectively. After the ether layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=100:1-10:1) to afford the title compound (19.4 g, 78% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7](CP(OC)(OC)=O)=[CH:6][CH:5]=1.CCC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CP(=O)(OC)OC)cc1
Agent: CCC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 2.0 g (6.6 mmol ) of 2,2,4,4,7,9,9-heptamethyl-3a,4,9,9a-tetrahydro-naphtho[2,3-d][1,3]-trans-dioxole-6-carbaldehyde and 2.2 g (8.6 mmol) of 4-(Dimethoxy-phosphorylmethyl)-benzoic acid methyl ester in 50 ml of toluene at 0° was added 5.6 ml of 1.7 M (8.6 mmol) of potassium tert-pentylate in toluene. After 1.5 h, poured into brine, extracted with ethyl acetate, dried over sodium sulfate and adsorbed onto silica gel. Purified by flash chromatography (gradient elution: hexane-2% ethyl acetae/hexane) to give 2.5 g (87%) of 4-[(E)-2-(2,2,4,4,7,9,9)-heptamethyl-3a,4,9,9a-tetrahydro-naphtho[2,3d][1,3]-trans-dioxol-6-yl)-vinyl]-benzoic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:42])([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[C:18]([N+:25]([O-])=O)[CH:17]=2)=[O:13])=[CH:6][CH:5]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:42])([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[C:18]([NH2:25])[CH:17]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N)cc(COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 70.1 %

Procedure:
4.99 g (8.38 mmol) of 3,5-dinitrobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]-methoxy}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 3.15 g of 3,5-diaminobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]-methoxy}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: N[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].N([O-])=O.[Na+]>>[S:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:2]=[C:3]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1sc2cccnc2c1N
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cc2ncccc2s1

Procedure:
HPLC. Using 2.40 g (11.53 mmol) of methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate and 2.54 g (36.88 mmol) of sodium nitrite, 0.12 g (5% of theory) of the desired product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S(O[CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)(C1C=CC(C)=CC=1)(=O)=O>>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCOCC1

Procedure:
In a similar manner to Example 1, 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine was reacted with 4-tosyloxytetrahydropyran to give after flash column chromatography 5-(4-phenoxyphenyl)-7-(4-tetrahydropyranyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 193-193.5° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:21]=[C:22]([N:26]([CH:30]([CH:39]2[CH2:41][CH2:40]2)[C:31]2[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=2)[CH2:27][CH2:28][CH3:29])[S:23][C:24]=1[CH3:25].CO>N1C=CC=CC=1.C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:21]=[C:22]([N:26]([CH:30]([CH:39]2[CH2:40][CH2:41]2)[C:31]2[CH:32]=[CH:33][C:34]([CH2:37][O:38][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([CH2:2][Cl:1])[CH:4]=3)=[CH:35][CH:36]=2)[CH2:27][CH2:28][CH3:29])[S:23][C:24]=1[CH3:25]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(CO)cc1)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(COC(=O)c2cccc(CCl)c2)cc1)C1CC1
Reaction time: 2 h
Yield: 81 %

Procedure:
0.6 ml of 3-chloromethylbenzoyl chloride is added dropwise, at 0° C., to 1.6 g of the compound of Example 4 dissolved in 10 ml of anhydrous pyridine. After 2 hours at 0° C., methanol is added to hydrolyze the excess acid chloride and the organic phase is diluted with methylene chloride. This is then washed with 2N hydrochloric acid, with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride and dried over anhydrous sodium sulphate. The organic solvent is evaporated off and the product is purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (20:1 v/v) as eluent, to give the expected product.
Reaction SMILES: ClC1C=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])(=[O:14])=[O:13].C[O-].[Na+].O1[CH2:41][CH2:40][O:39][CH2:38]C1>CCOC(C)=O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([NH:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][S:12]([C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:9])[F:11])[CH:6]=[CH:41][C:40]=2[O:39][CH3:38])(=[O:13])=[O:14])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)ccc1Cl)c1ccc(Cl)cc1
Reactant: C1COCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-[2-(4-chloro-benzenesulfonylamino)phenyl]-5-trifluoromethylbenzenesulfonamide (0.5 mmol) in dioxane (5 mL), solid sodium methoxide (2 mmol) was added in one portion and the resulting reaction mixture was then heated to reflux for ca. 4 h. After the completion of the reaction, the reaction mixture was cooled to RT and concentrated in vacuo. The residue obtained was redissolved in EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 160 mg of N-[2-(4-chlorobenzenesulfonylamino)phenyl]-2-methoxy-5-trifluoromethylbenzenesulfonamide. LC: Tr 1.22 min; MS: 521.8 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C@H:12]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C@H:12]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:10]
Reactant: O=C=Nc1ccccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Nc3ccccc3F)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1-fluoro-2-isocyanatobenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 517.0 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11](=[O:33])[CH:12]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20]C(OC(C)(C)C)=O)[CH:15]=1)[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([CH2:28][S:29][C:30](=[O:32])[CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1)[CH3:9]
Reactant: CCOC(=O)C(CSC(C)=O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CSC(C)=O)Cc1ccnc(N)c1
Reaction time: 1 h
Yield: 141.7 %

Procedure:
TFA (0.5 mL) was added to a solution of 2-acetylsulfanylmethyl-3-(2-tert-butoxycarbonylamino-pyridin4-yl)-propionic acid ethyl ester (50 mg, 0.13 mmol) in methylene chloride under argon. The solution was stirred for 60 min and concentrated under reduced pressure to give crude 2-acetylsulfanylmethyl-3-(2-amino-pyridin-4-yl)-propionic acid ethyl ester (52 mg, 100%).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[N:12](OCCCC)=[O:13]>COCCO>[N:12](=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[OH:13]
Reactant: CCCCON=O
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: COCCO
Product: O=C1C(=NO)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 134.5 %

Procedure:
1-Indanone (100 g, 0.757 mol) was dissolved in 2-methoxyethanol (600 mL) in a 2 L round bottom flask equipped with a overhead mechanical stirrer. The mixture was cooled over an ice bath, and concentrated aqueous HCl (200 mL) was added. Butyl nitrite (50 mL, 0.428 mol) was added, and after 1 minute when precipitate began to form, more butyl nitrite (50 mL, 0.428 mol) was added. The mixture was stirred for 15 min. more and then poured into ice water (8 L). The solid was filtered on a sintered funnel and rinsed with 8 L water. The solid was dissolved in 2.5 L hot methanol, seeded with pure oxime, then allowed to cool to room temperature then over an ice bath. The yellow crystals were collected on a sintered funnel, rinsed with cold methanol, then dried overnight under vacuum to yield 2-oximino-1-indanone (92.8 g, 76% yield). The finely ground oxime (80 g, 0.496 mol) was suspended in 35% formaldehyde solution (160 mL) and concentrated HCl (320 mL) in a 2 L round bottom flask equipped with an overhead mechanical stirrer. The temperature was maintained initially at 15° C. with an ice bath, then the bath was removed and the reaction mixture was stirred vigorously for 30 min. The mixture was poured onto 2 L ice, the solid filtered and then rinsed with water. The yellow powder was dried in a vacuum oven to yield 55.0 g product, which was recrystallized from ether (5 L, 3 crops) to afford after oven drying pure diketone (37.3 g, 51% yield). The aqueous mother liquor yielded crystals of the oxime (9.5 g, 12% recovered starting material).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[N:13]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[C:16]([F:26])[C:15]=2[F:27])[N:12]=[CH:11][CH:10]=1.O>C(O)(=O)C>[C:5]([NH:8][C:9]1[N:13]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[C:16]([F:26])[C:15]=2[F:27])[N:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
250 ml (0.26 mol) of acetic anhydride are added to 60 g (0.20 mol) of 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole in 170 ml glacial acetic acid, whereupon the reaction temperature rises from 20° C. to about 35° C. The mixture is stirred at room temperature for 16 hours and then poured onto 800 ml of water. The crystalline solid which has precipitated out is filtered off with suction, washed freely with water and acetic acid and dried in vacuo. 59.8 g (87.7% of theory) of 5-acetamido-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 102° C. -104° C. are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22]C(OC(C)(C)C)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31]>O1CCOCC1>[ClH:31].[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH2:22])[CH:18]=2)[NH:13][C:12]=1[CH3:30])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2ccc(CCNC(=O)OC(C)(C)C)cc2c1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 89 %

Procedure:
To a solution of 5-(2-tert-butoxycarbonylamino ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.972 g, 4.827 mmol) in dioxane (25 mL) at room temperature was added aqueous HCl (3.0 mL, 37%). The resulting mixture was then stirred at ambient temperature for 22 hours. After this duration, the mixture was concentrated in vacuo. Trituration with acetone gave 1.48 g (89%) of the desired product as a white solid, mp 282-283° C.; MS (APCI+): m/z 309.0 (M+1).
Reaction SMILES: C(P(CCCCCCCC)CCCCCCCC)CCCCCCC.[C:26]([Br:30])(Br)(Br)Br.[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42](CO)=[CH:41][C:40]=1[CH2:47][O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C(OCC)C>[Br:30][CH2:26][C:42]1[CH:43]=[CH:44][C:39]([O:38][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[C:40]([CH2:47][O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:50])[CH3:51])[CH:41]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C

Procedure:
In a manner similar to Example 3(b), by reacting 4.2 ml (9.4 mmol) of trioctylphosphine, 3.1 g (9.4 mmol) of carbon tetrabromide with 1.7 g (4.3 mmol) of [4-(tert-butyldimethylsilanyloxy)-3-(tert-butyldimethylsilanyloxymethyl)phenyl]methanol in 30 ml of ethyl ether, after purification on a silica column (AcOEt 10-Heptane 90), a yellow oil (m=1.7 g; Y=86%) is obtained.
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:29]([C:31]3[C:36]([NH2:37])=[CH:35][C:34]([F:38])=[C:33]([C:39]4[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=4[F:46])[N:32]=3)=[O:30])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.CO.[OH-].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[NH2:37][C:36]1[C:31]([C:29]([NH:28][C:12]2[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH2:20])[CH2:15]3)=[C:8]3[CH2:7][CH2:6][CH:5]([OH:4])[C:9]3=[N:10][CH:11]=2)=[O:30])=[N:32][C:33]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[C:34]([F:38])[CH:35]=1
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)c(F)cc1N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](N)C1)CCC2O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-({[3-Amino-6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (4.0 mg, 0.0062 mmol) was mixed with MeOH (74 μL), THF (37 μL) and 1.0 M NaOH (41 μL, 0.041 mmol). The reaction mixture was stirred at room temperature for 30 min. The organic solvents were removed under reduced pressure. The aqueous layer was diluted with aq. NH4Cl, then extracted twice with EtOAc. The combined organic layers were dried, filtered and concentrated under reduced pressure to give an intermediate, which was treated with DCM (0.064 mL) and TFA (0.064 mL, 0.82 mmol). The resulting mixture was stirred at room temperature for 30 min., then concentrated under reduced pressure. The residue was diluted with MeOH and neutralized with NH4OH. The resulting mixture was filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give two diastereoisomers of the title compound as white powders.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](N)[CH:8]=2)[CH:3]=[N:2]1.F[B-](F)(F)F.[H+].N([O-])=[O:18].[Na+]>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:18])[CH:8]=2)[CH:3]=[N:2]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Oc1ccc2cn[nH]c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Indazol-6-amine (24.33 g; manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in water (100 mL) and a 48 wt % aqueous solution of tetrafluoroboric acid (242 mL; manufactured by Sigma-Aldrich Co.), and the solution was cooled to 0° C. Subsequently, an aqueous solution of sodium nitrite (20 mL (sodium nitrite (13.87 g; manufactured by Kanto Chemical Co., Inc.) was dissolved in water (20 mL)) was added dropwise to the solution over 10 minutes, and the resulting mixture was stirred for 30 minutes at 0° C. Precipitates of the reaction solution were filtered, and were washed with chloroform. The obtained precipitates were dissolved in acetic acid (250 mL), and the solution was stirred for 10 minutes at 50° C., for 10 minutes at 110° C., and for 10 minutes at 130° C. The reaction solution was cooled, a saturated aqueous solution of sodium carbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in ethanol (240 mL). A 2 mol/L aqueous solution of sodium hydroxide (365 mL) was added to the solution, and the mixture was stirred for one hour at room temperature. The reaction solution was concentrated under reduced pressure, and 2 mol/L hydrochloric acid (200 mL), water and a saturated aqueous solution of ammonium chloride were added to the residue to adjust the pH to about 7. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine, and was dried over anhydrous magnesium sulfate. Subsequently, the solvent was evaporated under reduced pressure, and chloroform was added to the residue. Insoluble matters were filtered, and were washed with chloroform. Thus, a crude product (13.5401 g) of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].CC1(C)C(C)(C)OB([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)O1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:28][C:27]1[CH:29]=[CH:30][C:24]([C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[CH2:4][NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=[CH:25][CH:26]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C(NCc1ccccc1Br)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccccc2CNC(=O)C(F)(F)F)cc1
Temperature: 80 °C
Yield: 48.6 %

Procedure:
A mixture of N-(2-bromo-benzyl)-2,2,2-trifluoro-acetamide (282 mg, 1.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (284 mg, 1.3 mmol), Pd(OAc)2 (20 mg, 0.09 mmol) and PS—PPh3 (40 mg, 3 mmol/g, 0.12 mmol) was dissolved in DMF (5 mL) and 4M K2CO3 solution (0.5 mL) was added. The reaction was heated at 80° C. overnight. The mixture was filtered, concentrated and purified by column chromatography (0-50% ethyl acetate-hexanes) to yield N-(4′-amino-biphenyl-2-ylmethyl)-2,2,2-trifluoro-acetamide (1-1) (143 mg, 49%). HPLC ret. time 1.90 min, 10-99% CH3CN, 5 min run; ESI-MS 295.5 m/z (MH+).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][N:6]=1)=[O:4].[NH2:15][C:16]([CH3:21])([CH2:19][OH:20])[CH2:17][OH:18]>C(O)C>[OH:18][CH2:17][C:16]([NH:15][C:11]([C:8]1[CH:7]=[N:6][C:5]([C:3]([NH:15][C:16]([CH3:21])([CH2:19][OH:20])[CH2:17][OH:18])=[O:4])=[CH:10][N:9]=1)=[O:13])([CH3:21])[CH2:19][OH:20]
Reactant: COC(=O)c1cnc(C(=O)OC)cn1
Reactant: CC(N)(CO)CO
Solvent: CCO
Product: CC(CO)(CO)NC(=O)c1cnc(C(=O)NC(C)(CO)CO)cn1
Yield: 23.4 %

Procedure:
A solution of 500 mg of 2,5-dimethoxycarbonylpyrazine and 525 mg of 2-amino-2-methyl-1,3-propanediol in 3 cm3 of ethanol is heated at a temperature in the region of the reflux temperature for 90 minutes. The reaction mixture is filtered while hot. The white solid is washed with 5 cm3 of boiling ethanol. 200 mg of N,N′-bis(1,3-dihydroxy-2-methyl-2-propyl)pyrazine-2,5-dicarboxamide are thus obtained in the form of a white solid melting at 208° C. [1H NMR spectrum (400 MHz, CDCl3, δ at ppm): 1.34 (s, 6H: 2×CH3); 3.55 and 3.66 (2 dd, J=11 and 5.5 Hz, 8H: 4×OCH2); 5.01 (t, J=5.5 Hz, 4H: 4×OH); 8.22 (s, 2H: ═CH at 3 and ═CH at 6); 9.20 (s, 2H: 2×CONH)].