Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[CH3:11])[C:5](O)=[O:6]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[CH3:11]
Reactant: Cc1c(Cl)cc(C(=O)O)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1c(Cl)cc(CO)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
4.2 g of 3-chloro-4-methyl-5-nitro benzoic acid was dissolved in 20 ml dry THF and the solution was cooled to 0° C. BH3 -THF (28 ml) solution was added in 2 ml portions. After 1 hr, the reaction mixture was poured onto 100 g of ice containing saturated NaHCO3 solution. The mixture was extracted with ether (3×75 ml). The extracts were washed with brine, dried (anhydrous MgSO4), filtered, and concentrated. The resultant brown oil was applied to a SiO2 column as a solution in toluene and eluted with 25% ethyl acetate in hexane to give 1.96 g of (3-chloro-4-methyl-5-nitrophenyl)methanol.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[NH2:11][C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH:5]([NH:11][C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: Cn1nccc1N
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: Cn1nccc1NC=O
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
A mixture of acetic anhydride (38.86 ml) and formic acid (15.54 ml) was stirred at 45° C. for 45 minutes. To this mixture was added 5-amino-1-methylpyrazole (10 g) under ice-cooling, and the reaction mixture was stirred at the same temperature for 10 minutes. The resultant mixture was poured into a mixture of water and ethyl acetate, and the resultant solution was adjusted to pH 8 with potassium carbonate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate six times. The organic layers were combined, dried over magnesium sulfate, and evaporated in vacuo to give 5-formamido-1-methylpyrazole (12.88 g).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][O:13][C:14]([C:16]([F:22])([F:21])[S:17]([O-:20])(=[O:19])=[O:18])=[O:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:23]1([S+:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN1CCCC1.[CH3:48][C:49]([C:51](Cl)=[O:52])=[CH2:50].COC(C)(C)C>C(Cl)(Cl)Cl>[C:51]([O:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][O:13][C:14]([C:16]([F:22])([F:21])[S:17]([O-:20])(=[O:18])=[O:19])=[O:15])([CH2:5]3)[CH2:3]1)[CH2:9]2)(=[O:52])[C:49]([CH3:50])=[CH2:48].[C:36]1([S+:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(OCC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)S(=O)(=O)[O-]
Agent: CN1CCCC1
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)C
Product: C=C(C)C(=O)OC12CC3CC(CC(COC(=O)C(F)(F)S(=O)(=O)[O-])(C3)C1)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2.8 parts of triphenylsulfonium 1-((3-hydroxyadamantyl)methoxycarbonyl)difluoromethanesulfonate and 1.0 part of 1-methylpyrrolidine were dissolved in 30 parts of chloroform. A solution of 0.7 Part of methacryl chloride and 2.2 parts of chloroform was added dropwise to the solution at room temperature and then the resultant mixture was stirred at room temperature for about 3 days and at 40° C. for 7.5 hours. After cooling to room temperature, 1.0 part of 1-methylpyrrolidine was added to the reaction mixture and a solution of 0.7 part of methacryl chloride and 2.2 parts of chloroform was added thereto at room temperature. After reacting at room temperature for 14 hours, the reaction mixture was diluted with 30 parts of chloroform and quenched with 36 parts of ion-exchanged water in an ice bath. A chloroform layer was separated and repeatedly washed with ion-exchanged water. To the chloroform layer, 1.1 parts of active carbon was added and the mixture was stirred for 1 hour. The mixture was filtered and chloroform layer obtained was concentrated to obtain pale yellow oily matters. To the oily matters, tert-butyl methyl ether was added to stir and the mixture was filtered to obtain 2.8 parts of triphenylsulfonium 1-((3-methacryloyloxyadamantyl)methoxycarbonyl)difluoromethansulfonate in the form of white solid, which is called as TPS-4.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:25](=S)=[S:26]>N1C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:25]=[S:26])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1N=C=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 800 ml of pyridine were dissolved 275 ml of carbon disulfide and 93 ml of triethylamine. To the solution was added 125 g of 4-bromo-2-methylaniline. The mixture was stirred at room temperature overnight. Thereto was added 138.5 g of 1,3-dicyclohexylcarbodiimide (DCC). The mixture was stirred overnight. Pyridine was removed by distillation. To the residue was added n-hexane. The resulting precipitate (DC-thiourea) was removed by filtration. The filtrate was concentrated and the residue was purified by a silica gel column chromatography (eluant: n-hexane) to obtain 138 g of 4-bromo-2-methylphenyl isothiocyanate.
Reaction SMILES: Br[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[C:5]([OH:17])=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:3]=1.[CH3:23][Sn](C)(C)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.CN(C=O)C>[OH:17][C:5]1[C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[C:2]([CH3:23])=[N:3][C:4]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2c(-c3ccccc3)noc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2c(-c3ccccc3)noc2c1O
Temperature: 125 °C
Yield: 33.3 %

Procedure:
A nitrogen flushed flask was charged with ethyl 4-bromo-7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (150 mg, 0.413 mmol), DMF (2 mL), tetramethylstannane (0.17 mL, 1.24 mmol), and Pd(PPh3)2Cl2 (58 mg, 0.083 mmol). The mixture was heated in an oil bath (bath temperature=120-130° C.) for 2 hours. After the reaction mixture was cooled to room temperature, it was purified by flash chromatography (0-30% EtOAc/hexanes) to afford 41 mg of the title compound. MS: (+) m/z 299.43 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Agent: O=[Pt]
Solvent: CO
Product: O=C(O)C(O)Cc1ccc(O)cc1
Yield: 99.9 %

Procedure:
10 g of 3-(4-hydroxyphenyl)pyruvic acid were dissolved in 50 ml of methanol, and 0.05 g of platinum oxide was added thereto. The mixture was stirred at 25° C. under atmospheric pressure for 6 hours in a hydrogen stream. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 10.1 g of 3-(4-hydroxyphenyl)lactic acid as colorless crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH:11]=[CH:10][C@H:9]([NH:12][C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]3[CH:22]=[CH:23][S:24][C:14]=23)[CH2:8][O:7]1)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[C:18]([NH2:19])=[CH:17][N:16]=[C:15]3[CH:22]=[CH:23][S:24][C:14]=23)[CH2:8][O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1C=C[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CO1
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCC1CC[C@H](Nc2c(N)cnc3ccsc23)CO1
Yield: 75.2 %

Procedure:
A mixture of {(5S)-5-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]-5,6-dihydro-2H-pyran-2-yl}methyl acetate (210 mg, 0.600 mmol) and 10% palladium on carbon (0.21 g) in methanol (4.0 mL) was subjected to balloon pressure of H2 at room temperature for 2 h. The mixture was filtered, and the filtrate was concentrated and purified with flash chromatography (eluting with 15% methanol in dichloromethane) to give the desired product (145 mg, 75%). LCMS calculated for C15H20N3O3S (M+H)+: m/z=322.1. Found: 322.0.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][Si:9]([CH3:12])([CH3:11])Cl>C1COCC1.C[N-]C1C=CC=CC=1.C1([Mn+])C=CC=CC=1>[CH3:8][Si:9]([CH3:12])([CH3:11])[O:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCCCC1
Agent: [Mn+]c1ccccc1
Agent: C[N-]c1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=CCCCC1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
- In another experiment, an enolate is prepared by the reaction of 100 mmol of phenylmanganese N-methyl-N-phenylamide: ##STR11## with 100 mmol of cyclohexanone in 200 ml of THF at 20° C. for 1 hour: ##STR12## 100 mmol of trimethylchlorosilane, ClSiMe3, are added to the resulting solution at 20° C. and the mixture is stirred for 30 minutes to produce the following reaction: ##STR13## 1-Trimethylsilyloxycyclohexene is obtained with a yield of 59%, compared with 77% for procedure A.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:21]1([OH:24])[CH2:23][CH2:22]1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([C:21]2([OH:24])[CH2:22][CH2:23]2)[CH2:12][CH3:13])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(c1ccc(Cl)cc1)(n1ccc2c(N)cccc21)C1(O)CC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(c1ccc(Cl)cc1)(n1ccc2c(NS(C)(=O)=O)cccc21)C1(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of compound from step B (83 mg, 0.22 mmol) and NMM (44 mg, 0.44 mmol) in DCM (5 mL) was added methylsulfonyl chloride (37 mg, 0.3 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by Pre-HPLC to afford the title compound as a white solid. LC/MS m/z=419.1[M+H]+.
Reaction SMILES: Br[CH:2]([C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:7]=1)[CH3:3].[NH2:20][OH:21]>CN1CCCC1=O.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([C:5]#[C:4][CH:2]([NH:20][OH:21])[CH3:3])[CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: CC(Br)C#Cc1cccc(Oc2ccc(F)cc2)c1
Reactant: NO
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)NO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The 2-bromo-4-[3-(4-fluorophenoxy)phenyl]-3-butyne prepared in step 2 was taken up in N-methyl-2-pyrollidinone (27 kg) and 50% aqueous hydroxylamine (21 kg) was added. The reaction mixture was agitated for 2.5 hours at ambient temperature and then was diluted with distilled water (18 kg). The layers were separated and the organic phase was concentrated in vacuo to give N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]hydroxylamine.
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.O>CN(C=O)C>[I:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Ic1cccc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc2c(I)cccc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 78.2 %

Procedure:
To a stirring solution of 4-iodo-1H-benzimidazole (1.00 g, 4.1 mmol) in DMF (12 mL) was added sodium hydride (180 mg of a 60% dispersion in mineral oil; 4.5 mmol), and the resulting mixture was stirred at room temperature under nitrogen for 50 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (870 μL, 4.92 mmol) was added dropwise over 5 minutes at room temperature, then the mixture was stirred overnight. Water (50 mL) was added, and the mixture was washed with ethyl acetate (3×25 mL). The combined organic layers were washed with water (2×30 mL), then with saturated sodium chloride solution (30 mL), then dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 0 to 20% ethyl acetate in dichloromethane, affording the product as a white solid (1.20 g, 78%). 1H NMR (400 MHz, CDCl3): δ 8.05 (1H, s), 7.74 (1H, dd, J=0.6, 7.5 Hz), 7.52 (1H, t, J=4.2 Hz), 7.09 (1H, t, J=7.9 Hz), 5.51 (2H, s), 3.50 (2H, t, J=8.2 Hz), 0.90 (2H, dd, J=8.3, 16.4 Hz), −0.05 (9H, s); m/z (ES+) 375 [MH+].
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH:6]=1)=[N+]=[N-].Cl.[Cl:25]C(Cl)C.C(OCC)(=O)C>[Pt](=O)=O>[ClH:25].[NH2:1][CH2:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH:6]=1
Reactant: CC(Cl)Cl
Reactant: [N-]=[N+]=NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
In a 50 mL round bottom flask, 3-azidomethyl-7-fluoro-1-(2-fluoro-phenyl)-1H-quinolin-4-one (0.290 g, 0.929 mmol) was added platinum (IV) oxide (0.040 g, 0.176 mmol) and 4 N HCl (2 mL) in 1:1 dichloroethane-ethyl acetate (15 mL). The reaction was charged with 1 atm. H2 using a balloon and stirred at room temperature for 3 hr. The catalyst was filtered off and the filtrate evaporated to dryness to give 3-aminomethyl-7-fluoro-1-(2-fluoro-phenyl)-1H-quinolin-4-one hydrochloride salt (200 mg, 67% yield). The crude was used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:26][C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[N:3]=1)[O:10][CH2:9][C@H:8]([CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O)[O:7]3.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][CH2:14][C@H:8]2[CH2:9][O:10][C:11]3[CH:12]=[CH:13][C:4]4[N:3]=[C:2]([CH3:1])[O:26][C:5]=4[C:6]=3[O:7]2)[CH2:39][CH2:38]1
Reactant: N[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc32)CC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)O[C@@H](CN[C@H]1CC[C@@H](c2c[nH]c4ccc(F)cc42)CC1)CO3
Temperature: 80 °C

Procedure:
Toluene-4-sulfonic acid (8R)-2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthlen-8-ylmethyl ester (0.52 g, 1.39 mmole) and cis-4-(5-fluoro-1H-indol-3-yl)-cyclohexylamine (0.60 g, 2.6 mmole) were combined in 10 mL of anhydrous DMSO under nitrogen. This solution was heated to 80° C. under nitrogen for 5 hours. After cooling to room temperature, the reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel (CH2Cl2 then 1% MeOH/CH2Cl2) afforded 0.26 g of the title compound as a light yellow solid: m.p. 80-82° C.; MS (ESI) m/z 436 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20](O)=[O:21])=[CH:11][CH:10]=1.S(Cl)(Cl)=O.[NH:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=[O:33].C([O-])([O-])=O.[Na+].[Na+].Cl>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([N:30]2[CH2:37][CH2:36][CH2:35][C@H:31]2[C:32]([OH:34])=[O:33])=[O:21])=[CH:13][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(O)[C@@H]1CCCN1C(=O)c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 90.8 %

Procedure:
3-(2′,4′-Difluoro-biphenyl-4-yloxymethyl)-benzoic acid (4.0 g, 11.76 mmol) in 125 mL toluene was treated with thionyl chloride (8.28 mL, 117.6 mmol) and DMF (200 uL) was heated to 80-90° C. for 3 hrs. The reaction mixture was cooled, evaporated and re-evaporated from toluene 4 times to give a yellow oil that crystallized by pumping under high vacuum. This acid chloride was dissolved in 160 mL acetonitrile to which was added a solution of L-proline (2.62 g, 22.8 mmol) in 33 mL H2O and 1N Na2CO3 (22.8 mL, 22.8 mmol). The reaction mixture was stirred at RT for 45 min, diluted with 300 mL H2O and 450 mL ethyl acetate. The mixture was acidified to pH 2 with 1N HCl. The ethyl acetate layer was separated, washed with H2O, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography with a 0-90% gradient of ethyl acetate/MeOH/AcOH (95:5:1) in hexanes to yield 4.67 g (90.8%) of (S)-1-[3-(2′,4′-difluoro-biphenyl-4-yloxymethyl)-benzoyl]-pyrrolidine-2-carboxylic acid as a white solid. LC-MS (ES) calculated for C25H21F2NO4, 437.45; found m/z 438.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH:33]([C:36](Cl)=[O:37])([CH3:35])[CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:36](=[O:37])[CH:33]([CH3:35])[CH3:34])[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(=O)Nc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125, 18 mg, 0.042 mmol) in CH2Cl2 (1 ml) was added i-PrCOCl (8.7 μl, 0.089 mmol) and DMAP (10 mg, 0.089 mmol). The reaction was stirred at room temperature for 2 h, diluted with EtOAc, washed with aqueous Na2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]([C:14]([OH:16])=O)=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]>O1CCCC1>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:9]2[C:8]([CH2:14][O:16][C:10]2=[O:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc(Oc2ccc(F)cc2F)c([N+](=O)[O-])cc1C(=O)O
Solvent: C1CCOC1
Product: O=C1OCc2cc([N+](=O)[O-])c(Oc3ccc(F)cc3F)cc21
Yield: 31.2 %

Procedure:
As described in Example 9(a), 4.6 g of 5-(2,4-difluorophenoxy)-4-nitrophthalic acid in 20 ml of absolute tetrahydrofuran is reduced with 100 ml of a 0.3-molar borane-tetrahydrofuran complex solution in tetrahydrofuran and worked up. Crystallization from ethanol yields 1.3 g of 6-(2,4-difluorophenoxy)-5-nitrophthalide, mp 164°-165.5° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C@H:28]([O:30][CH2:31][C@H:32]([O:43][C:44]1[N:49]=[CH:48][N:47]=[C:46]2[N:50]([C:53]3[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][N:54]=3)[N:51]=[CH:52][C:45]=12)[C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=1)=[O:34])[CH3:29])(C(C)(C)C)(C)C>C1COCC1>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([NH:35][C:33](=[O:34])[C@@H:32]([O:43][C:44]2[N:49]=[CH:48][N:47]=[C:46]3[N:50]([C:53]4[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][N:54]=4)[N:51]=[CH:52][C:45]=23)[CH2:31][O:30][C@H:28]([CH3:29])[CH2:27][OH:26])=[N:37][CH:38]=1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CO)OC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.892 mL, 0.89 mmol) was added to (2S)-3-((R)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-N-(5-chloropyridin-2-yl)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (Intermediate AN4) (460 mg, 0.74 mmol) in THF (5 mL) under nitrogen. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (10 mL), extracted with EtOAc (3×15 mL), the combined organic layers were back washed with water (10 mL), dried (MgSO4), and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 90% EtOAc in isohexane to afford the product (256 mg, 68.3%). 1H NMR (400 MHz, DMSO) δ1.07 (d, 3H), 3.26-3.37 (m, 1H), 3.38-3.47 (m, 1H), 3.61-3.71 (m, 1H), 4.07-4.18 (m, 2H), 4.57 (t, 1H), 5.87-5.93 (m, 1H), 7.74-7.79 (m, 1H), 7.88-7.93 (m, 1H), 8.00-8.06 (m, 1H), 8.32-8.37 (m, 1H), 8.41 (d, 1H), 8.57 (s, 1H), 8.66 (s, 1H), 8.67-8.70 (m, 1H), 11.15 (s, 1H) m/z (ESI+) (M+H)+=504.37; HPLC tR=1.96 min
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH:31]1[CH2:34][O:33][CH2:32]1.C(=O)([O-])O.[Na+]>C(O)(C)C.[Ni](I)I.N[C@@H]1CCCC[C@H]1O>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:31]2[CH2:34][O:33][CH2:32]2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(B(O)O)c1
Reactant: IC1COC1
Agent: I[Ni]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N[C@@H]1CCCC[C@H]1O
Solvent: CC(C)O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(C2COC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4.6 g of 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-phenylboronic acid, 130 mg of nickel iodide, 5.0 g of sodium bis(trimethylsilyl)amide and 62 mg of (1R,2R)-2-aminocyclohexanol were placed in a microwave vial and 3.5 ml of isopropanol were added. The mixture was stirred for 10 min at room temperature. Then a solution of 3-iodooxetane in 1.5 ml of isopropanol was added and the mixture treated under microwave irradiation at 80° C. for 30 min. The obtained mixture was combined with the mixtures obtained in three further runs of the synthesis, poured into 50 ml of a saturated aqueous sodium hydrogencarbonate solution and extracted three time with 50 ml each of EA. The combined organic layers were dried with magnesium sulfate and evaporated to yield 9.0 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH:29]2[C:24]([CH2:25][NH:26][CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>CN(C)C=O>[CH3:30][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([CH2:34][CH:31]3[CH2:33][CH2:32]3)[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:22])([OH:23])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CNCCC3C(C)(C)OC2=C1
Reactant: BrCC1CC1
Solvent: CN(C)C=O
Product: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CN(CC4CC4)CCC3C(C)(C)OC2=C1

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano[4,3-c]pyridin-10-ol (1 mole) and cyclopropylmethylbromide were reacted in dimethylformamide as described in Example 7 to give the desired product.