Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH2:4][C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:56]=[CH:55][C:52]([CH2:53][NH2:54])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:50]=[CH:51][C:52]([CH2:53][NH:54][C:5](=[O:6])[CH2:4][CH:3]([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:55][CH:56]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=C(O)CC(C(F)(F)F)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CNC(=O)CC(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.2 %

Procedure:
A solution of 2.1 g of 4,4,4-trifluoro-3-trifluoromethyl-butyric acid (10 mmol) in 80 ml DMF was treated with 3.12 g of TBTU (10 mmol) and 8.55 ml of N,N-diisopropylethyl amine and stirred for 5 min at rt under argon. Then 1.93 ml of 4-tert-butylbenzylamine (11 mmol) were added and the reaction mixture was stirred 17 h at rt. The reaction mixture was then diluted with 400 ml water and extracted twice with EtOAc, the combined organic phases washed with brine, dried over magnesium sulfate filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; heptane/EtOAc 4:1) to give 2.14 g of N-(4-tert-butyl-benzyl)-4,4,4-trifluoro-3-trifluoromethyl-butyramide as a light yellow solid (60%).
Reaction SMILES: [CH3:1][C:2](O)([C@@H:4](/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[CH2:20][C@@H:21]2O)=[CH:16][CH:15]=3)[CH2:12][CH2:11]1)[CH3:9])C)[CH3:3].[N+]([O-])([O-])=O.[K+]>CCOCC.O1CCCC1>[CH3:23][C:22]1[CH2:21][CH2:20][C@H:19]([OH:30])[CH2:18][C:17]=1/[CH:16]=[CH:15]\[C:14]1[C@@H:13]2[CH2:12][CH2:11][C@H:10]([C@@H:8]([CH2:7][CH2:6][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:9])[C@@:27]2([CH3:28])[CH2:26][CH2:25][CH:24]=1
Reactant: C[C@H](/C=C/[C@@H](C)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=C(/C=C\C2=CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)CC1
Yield: 31.7 %

Procedure:
(24R,22E)-5,7,22-Ergostatrien-1α,3β,25-triol (Ib) (100 mg, 0.23 mmol) was dissolved in a mixed solution of ether (950 ml) and tetrahydrofuran (50 ml), and the solution was irradiated with high pressure mercury lamp using an 1.5% aqueous potassium nitrate solution as a filter with water cooling in a nitrogen stream for 3 minutes. The residue obtained by distilling off the solvent from the reaction solution was purified by HPLC (column: Lichrosorb® Si60 (7 μm), φ25×250 mm, Merck Co., Ltd.; column effluent: 5% methanol/methylene chloride; flow rate: 8.0 ml/min; detected at 265 nm) to give 28 mg of the previtamin D.
Reaction SMILES: [N:1]1([CH2:6][C@H:7]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[O:8][C:9]2[C:10]([N+:20]([O-])=O)=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.CO.C(O)(=O)C.C([O-])(O)=O.[Na+]>[Fe].CCOC(C)=O.O>[NH2:20][C:10]1[C:9]([O:8][C@@H:7]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][C:15]2=[O:19]
Reactant: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1cccnc1)c2[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1c(O[C@H](Cn2ccnc2)c2cccnc2)ccc2c1CCCC2=O
Reaction time: 4 h
Yield: 46.6 %

Procedure:
A mixture of 6-((S)-2-Imidazol-1-yl-1-pyridin-3-yl-ethoxy)-5-nitro-3,4-dihydro-2H-naphthalen-1-one (1.60 g, 4.23 mmol), MeOH (85 mL), H2O (19 mL) and glacial acetic acid (2.4 mL, 42 mmol) was treated at reflux with iron powder (2.34 g, 42 mmol). The reaction was monitored by mass spectrometry and was complete in 4 h. The volume of solvent was reduced under reduced pressure. EtOAc and dilute aqueous NaHCO3 were added. A brownish-green emulsion formed which was filtered through Celite. The mixture was extracted with EtOAc. The combined organic layer was washed with dilute aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated under reduced pressure to give an off-white foam (0.685 g, 1.97 mmol, 46%). The structure was confirmed by NMR and mass spectrometry. MS m/z 349 (M++H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[S:11][C:10]([C:12]3[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Na].[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.[OH-].[Na+]>C(O)(=O)C.O>[N:1]1([CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCC(c2ccc(Cn3ccnc3)s2)=NN1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccc(Cn3ccnc3)s2)n[nH]1

Procedure:
20 g of 4.5-dihydro-6-[5-(imidazol-1-yl-methyl)-thien-2-yl]-3(2H)-pyridazinone (EP No. 71 059, Example 1) are stirred under reflux together with 19.5 g of the sodium salt of 3-nitrobenzenesulfonic acid and 13.5 g of sodium hydroxide in b 250 ml of water for 1 hour. Thereafter, while the solution is still hot, acetic acid are added until pH 6.9. The solid material precipitated after cooling is filtered of with suction, washed with water and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:10]=[C:11]([O:13][CH2:14][CH2:15][OH:16])[CH:12]=2)[CH:9]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+]>O>[N+:1]([C:4]1[CH:9]=[C:12]2[C:11]([O:13][CH2:14][CH2:15][OH:16])=[N:10][NH:8][C:7]2=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2cc(OCCO)nn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cnc2[nH]nc(OCCO)c2c1
Yield: 9.3 %

Procedure:
Nitromalonaldehyde sodium salt monohydrate (1.46 g, 9.29 mmol) was added to crude 2-(5-amino-1H-pyrazol-3-yloxy)ethanol (3.28 g) with salts (1.33 g, 9.29 mmol theoretical) in acetic acid (10 mL). This was heated at 90° C. for 2 hours. The cooled reaction mixture was diluted with water, and the mixture was extracted twice with DCM containing 25% IPA. The organic extracts were dried over magnesium sulfate, filtered, and evaporated to yield regioisomer 2-(6-nitropyrazolo[1,5-a]pyrimidin-2-yloxy)ethanol (0.77 g, 3.43 mmol) as a solid. The 2-(6-nitropyrazolo[1,5-a]pyrimidin-2-yloxy)ethanol (460 mg, 2.9 mmol) was suspended in water (40 mL), treated with saturated aqueous sodium bicarbonate (2 mL), and the mixture was refluxed for 2 hours. The cooled reaction mixture was extracted three times with DCM containing 25% IPA. The organic extracts were dried over magnesium sulfate, filtered, and evaporated to an oil. The crude material was purified by column chromatography with ethyl acetate to provide 2-(5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yloxy)ethanol (60 mg, 0.27 mmol, 2.9% yield) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li][N:38]([Si](C)(C)C)[Si](C)(C)C>CCOC(C)=O.Cl>[NH2:38][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc(Cl)nc1
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Agent: Cl
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(N)nc1
Temperature: 90 °C
Yield: 95.4 %

Procedure:
In a flame-dried seal tube reaction vial, under argon atmosphere, add 2-(6-Chloro-pyridin-3-yl)-propan-2-ol (750 mg, 4.375 mmol), 2-(dicyclohexylphosphino)-biphenyl (307 mg, 0.875 mmol) and then add LiN(TMS)2 (1M in THF, 13.5 mL, 13.5 mmol). Seal the tube and heat it up to 90° C. for 18 hours. The dark reaction mixture was then diluted with EtOAc (10 mL). HCl (2M) (10 drops) was added with stirring. The reaction mixture was then concentrated and loaded onto ISCO separation column and eluted with 5% MeOH/(1/1 EtOAC/Hex) to afford 2-(6-Amino-pyridin-3-yl)-propan-2-ol as solid (635 mg, yield 95%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].[C:15]([O-:18])([O-])=[O:16].[K+].[K+]>C1COCC1.O.CCOC(C)=O>[C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH2:10][CH2:11]1)([O:18][C:3]([CH3:8])([CH3:4])[CH3:1])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C#N)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 174.3 %

Procedure:
To a solution of (2-cyano-phenyl)-piperazine (2.4 g, 12.78 mmol) in THF and H2O (25 mL, 1:1) was added K2CO3 (3.9 g, 28.12 mmol). The solution was allowed to stir for about 10 minutes at r.t. Boc-anhydride (3.1 g, 14.06 mmol) was then added and reaction was allowed to stir for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with sat. NaHCO3 (100 mL) and brine (100 mL). The organic phase was concentrated to dryness yielding 3.2 g of 1-Boc-4-(2-cyano-phenyl)-piperazine (88%). To a solution of sodium borohydride (2.1 g, 56.03 mmol) in THF (25 mL) at 0° C. was added TFA (4.3 mL, 56.03 mmol) dropwise. 1-Boc-4-(2-cyano-phenyl)-piperazine (3.2 g, 11.21 mmol) was then added slowly at r.t. The reaction was allowed to stir for about 12 hours at r.t. The reaction was quenched with H2O, diluted five-fold with EtOAc and washed with brine. The organic phase was concentrated to dryness yielding about 1.0 g of 1-Boc-4-(2-aminomethyl-phenyl)-piperazine (30%). MS (ESI+) 292.1 (M+1)
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[C@@H:13]([CH3:32])[CH2:12]1)C1C=CC=CC=1>C(O)C>[CH3:30][N:28]([CH3:29])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:11]([NH2:10])[CH2:12][C@@H:13]2[CH3:32])=[O:31])=[CH:27][CH:26]=1
Reactant: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Solvent: CCO
Product: C[C@H]1C[C@@H](N)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Reaction time: 18 h
Yield: 91.8 %

Procedure:
(±)-Cis-[1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic acid benzyl ester (665 mg, 1.49 mmol) was dissolved in ethanol (30 mL). The resulting solution was evacuated and backfilled with argon. A catalytic amount of palladium on carbon (10%) was added. The vessel was once again evacuated and this time was backfilled with hydrogen from a balloon. The reaction was then allowed to react at room temperature over night under a hydrogen atmosphere. Reaction was complete after 18 h. The mixture was carefully filtered and concentrated to 10% volume. The resulting concentrated solution was filtered through an Acrodisc® and concentrated to afford the crude amine (423 mg, 92%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15]>N1C=CC=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[S:15])[CH:3]=[CH:4][NH:5]2)=[CH:10][CH:9]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc2c(O)ccnc2c1
Solvent: c1ccncc1
Product: COc1ccc2c(=S)cc[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Hydroxy-7-methoxyquinoline (2.3 g, 13 mmol) dissolved in pyridine (30 ml) was added with phosphorus pentasulfide (2.9 g, 13 mmol) and refluxed for an hour. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residues were added with water (80 ml) and stood at 0° C. for about 30 minutes. The resulting precipitates were collected by filtration, washed with water and recrystallized from mixed solvent (about 60 ml) of ethanol with water (2 : 1) to obtain 1.7 g (68%) of the titled orange compound.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9](=O)[C:8]3[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>C(O)CO>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8]3[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2c(Cl)cccc2-c2ccccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Clc1cccc2c1CCCc1ccccc1-2
Temperature: 0 °C

Procedure:
Under a dry nitrogen atmosphere a stirred mixture of 8-chloro-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-5-one (2.6 grams, 0.011 mole), 85% hydrazine hydrate (5 ml, 0.1 mole), potassium hydroxide (4 grams, 0.071 mole) and ethylene glycol (30 ml) was heated at reflux for 1.5 hours. Sufficient volatiles were removed by distillation to increase the pot temperature to 200° while maintaining reflux. The two-phase reaction mixture was refluxed at that temperature for three hours. The mixture was cooled, poured into ice water, and the resultant mixture extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give a yellow oil. The oil was purified by distillation to give 4-chloro-6,7-dihydro-5H-dibenzo[a,c]cycloheptene (bp 119°-126°/0.15 mm).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:21][C:20](=[N:22][O:23][CH3:24])[C:16]5([CH2:19][NH:18][CH2:17]5)[CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:30](O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:21][C:20](=[N:22][O:23][CH3:24])[C:16]5([CH2:19][N:18]([CH3:30])[CH2:17]5)[CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CNC2
Reactant: CCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CN(C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
1-Cyclopropyl-6-fluoro-7-[8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was added to 10 ml of ethanol, and thereto 0.2 ml of acetic acid was dropped and 42 mg of p-formaldehyde was added. The mixture was stirred at room temperature for 30 minutes, and thereto 85 mg of sodium cyanoborohydride was added. It was stirred at room temperature for 2 hours. The resulting precipitate was filtered and dried to give 260 mg of the titled compound (yield: 83.7%).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BrH:11].Br.[CH3:13][N:14]([CH3:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:21][NH2:22])=[NH:20]>C(O)C>[BrH:11].[BrH:11].[N+:1]([C:4]1[O:8][C:7]([CH:9]=[N:22][NH:21][C:19](=[NH:20])[NH:18][CH2:17][CH2:16][CH2:15][N:14]([CH3:23])[CH3:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C)CCCNC(=N)NN
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: Br
Solvent: CCO
Product: CN(C)CCCNC(=N)NN=Cc1ccc([N+](=O)[O-])o1

Procedure:
5-Nitro-2-furaldehyde (0.564 g, 4 mmole) and N-(3-dimethylaminopropyl)hydrazinecarboximidamide dihydrobromide (1.6 g, 5 mmole) are heated at reflux in 8 ml 95% ethanol for 1 hour. The title compound precipitates from solution on cooling and is recrystallized from ethanol, mp 131°-133° C.
Reaction SMILES: CN1CCOCC1.[C:8]([OH:11])(=[O:10])[CH3:9].Cl[CH:13]([O:15][C:16]([CH2:18][NH:19][CH2:20][C:21]([O:23][CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:49])[C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:47])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:46])=[CH:34][C:33]=2[CH3:48])[C:26]2[CH:50]=[CH:51][C:52]([Cl:54])=[CH:53][C:25]1=2)=[O:22])=[O:17])[CH3:14]>O>[C:8]([O:11][CH:13]([O:15][C:16]([CH2:18][NH:19][CH2:20][C:21]([O:23][CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:49])[C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:47])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:46])=[CH:34][C:33]=2[CH3:48])[C:26]2[CH:50]=[CH:51][C:52]([Cl:54])=[CH:53][C:25]1=2)=[O:22])=[O:17])[CH3:14])(=[O:10])[CH3:9]
Reactant: CC(=O)O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CNCC(=O)OC(C)Cl)c3cc(Cl)ccc32)c(C)c1
Solvent: O
Solvent: CN1CCOCC1
Product: CC(=O)OC(C)OC(=O)CNCC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.4 %

Procedure:
N-methylmorpholine (0.31 ml, 2.8 mmol) was added dropwise to an acetic acid (0.32 ml, 5.6 mmol) solution of 7-chloro-1-[2-methyl-4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl [(1-chloroethoxycarbonyl)methylamino]acetate (0.35 g, 0.56 mmol) under cooling with ice, and the mixture was stirred at room temperature for two days. Water was added to the reaction mixture, and then the resulted precipitates were collected by filtration and air-dried. The dried product was purified by silica gel chromatography (n-hexane:ethyl acetate) to obtain 0.26 g (72%) of 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl [(1-acetoxy-ethoxycarbonyl)methylamino]acetate as amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]([O:30][Si](C)(C)C)=[CH:28][CH3:29]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:28]([CH3:29])[C:27]([O:26][CH3:25])=[O:30])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC=C(OC)O[Si](C)(C)C
Reactant: OC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
(a)(b) To a solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (800 mg, 2.5 mmol) and (1-methoxyprop-1-enyloxy)trimethylsilane (1 mL, 6.25 mmol) in 30 mL of dry DCM was added TiCl4 (2.5 mL of 1.0 M DCM solution, 2.5 mmol) and then stirred 1 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, concentrated to give methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoat. Crude methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoate was heated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 770 mg (82% yield, 2 steps) of acid 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid. MS found: (M+H)+=375.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH2:23].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH:23][C:25](=[O:26])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.2 %

Procedure:
N,N-diisopropylethylamine (0.745; 4.33 mmol) was added to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.500 g; 2.16 mmol), and phenyl chloroformate (0.406 mL; 3.25 mmol) in dichloromethane (20 mL). The solution was stirred at room temperature for 20 minutes, diluted in dichloromethane, washed with sodium hydrogen sulfate (1M, water), sodium carbonate (1M, water) and brine. The organic layer was dried and concentrated under reduced pressure to furnish 0.60 g (88%) of phenyl 2-(5-chloro-1H-indol-3-yl)ethylcarbamate as a yellow oil.
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[Mn]([O-])(=O)(=O)=O.[K+].[CH:14]([NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1)=[O:15]>C(O)(=O)C>[CH:14]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[O:3])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1)=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cc1csc(NC=O)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCOC(=O)Cc1csc(=NC=O)[nH]1
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of manganous acetate tetrahydrate (120 g.), acetic acid (1000 ml) and acetic anhydride (100 ml.) was stirred for 20 minutes in an oil bath heated at 130° to 135° C., and to the mixture was added potassium permanganate (20 g.) over 5 minutes at 105° to 110° C. with stirring and then the mixture was further stirred for 30 minutes at 130° to 135° C. The mixture was cooled to room temperature, and to the mixture was added ethyl 2-(2-formylaminothiazol-4-yl)acetate, which can be represented as ethyl 2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetate, (53.5 g.), and then the mixture was stirred for 15 hours at 38° to 40° C. under introduction of air at the rate of 6000 ml. per minute. After the reaction, the precipitates were collected by filtration. The precipitates were washed with acetic acid and water in turn and then dried to give ethyl 2-(2-formylaminothiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-formylimino-2,3-dihydrothiazol-4-yl)glyoxylate, (41.5 g.), mp 232° to 233° C. (dec.).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:26])=[O:25]
Reactant: OCC(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 96.8 %

Procedure:
In a 500 mL three-opening flask, 2,2-diphenyl ethanol (17 g, 86 mmol) was dissolved in 170 mL dichloromethane. To the flask was added triethylamine (13.03 g, 129 mmol). The resulting mixture was stirred at 0° C. for half an hour. To the resulting mixture was slowly added MsCl (11.92 g, 104 mmol) dropwisely. The reaction was conducted at 25° C. After the completion of reaction monitored by TLC, the reaction solution was washed with water thrice. The organic phase was dried over anhydrous sodium sulfate and evaporated to remove the solvent to produce 2,2-diphenylethyl methanesulfonate (23 g) in a yield of 96.78%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].C(N(C(C)C)CC)(C)C.Cl.[CH3:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>C(#N)C>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][CH3:22]
Reactant: COCCCCN
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCNc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 90 h
Yield: 66.6 %

Procedure:
To a solution of 1,3-difluoro-2-nitrobenzene (3.00 g) and diisopropylethylamine (7 μl) in acetonitrile (30 ml) was added a solution of 4-methoxybutan-1-amine hydrochloride (2.51 g) in acetonitrile (10 ml), and the mixture was stirred at room temperature for 90 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (2:98-25:75) was concentrated under reduced pressure to give the object product (2.90 g).