Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[OH:7].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl.C(OCC)C>N1C=CC=CC=1>[C:8]1([CH:6]([OH:7])[CH2:5][O:4][CH2:3][CH2:2][O:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: OCCOCC(O)c1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCOCC(O)c2cccc3ccccc23)cc1
Temperature: -25 °C
Reaction time: 4 h

Procedure:
8.3 g of 2-(2-hydroxyethoxy)-1-(1-naphthyl)ethanol was dissolved in 50 ml of pyridine. The solution was cooled to -25° C. Thereto was added 6.8 g of p-toluenesulfonyl chloride. The resulting mixture was allowed to stand at 0°-5° C. for 24 hours and further at room temperature for 4 hours. The reaction mixture was added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 20 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 6.3 g of colorless, oily 1-(1-naphthyl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.O.C(=O)(O)[O-].[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[C:3]([Cl:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(Cl)ccc2ccncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1c(Cl)ccc2ccncc12

Procedure:
8-Amino-7-chloroisoquinoline is refluxed in excess acetic anhydride for 2 hours or until the reaction is complete. The mixture is then poured into water, neutralized with 10% aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and concentrated to give 8-acetamido-7-chloroisoquinoline.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.Cl.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2ncc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a flask charged with Pd(PPh3)4 (46 mg, 0.040 mmol) under nitrogen was added a solution of 6-(1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (130 mg, 0.40 mmol) in DMF (5 mL). The system was purged with nitrogen gas three times and then tributyl-(1-ethoxy-vinyl)-stannane (0.14 mL, 0.42 mmol) was added. The temperature was increased to 100° C. and stirred for 2 h. Then the reaction mixture was cooled to rt, 3N HCl was added and the mixture was stirred for additional 4 h. Water was added and the product was then extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in DCM) to afford 120 mg (90%) of the title compound. LCMS (method B): [MH]+=335, tR=2.41 min.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)C1SC=CN=1.C([Sn](Cl)(CCCC)CCCC)CCC.C[Si](C)(C)[C:31]1[S:32][C:33]([Sn:36]([CH2:45][CH2:46][CH2:47][CH3:48])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:34][N:35]=1>CCOCC.C(Cl)(Cl)Cl.CO>[CH2:45]([Sn:36]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[C:33]1[S:32][CH:31]=[N:35][CH:34]=1)[CH2:46][CH2:47][CH3:48]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C)(C)C)s1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)c1nccs1
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: CCCC[Sn](CCCC)(CCCC)c1cncs1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (1.6M, 4.95 mL, 7.88 mmol) was added to a solution of 2-trimethylsilylthiazole (826 mg, 5.25 mmol) in anhydrous ether (45 mL) stirred at −78° C. under nitrogen. After 20 min, tri-n-butylstannyl chloride (2.57 g, 7.88 mmol) was added, then the solution was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give a brown oily residue. The residue of 2-trimethylsilyl-5-tributylstannyl-thiazole was passed through a column of neutral alumina eluting with a gradient of ammoniated methanol in chloroform to give the sub-title compound as a yellow oil (1.5 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H][H]>C(O)C.[Pd]>[NH2:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(N)CCc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(N)CCc1ccccc1N

Procedure:
A solution of ethyl 2-amino-4-(2-nitrophenyl)butyrate (27 g) in ethanol (600 ml) was hydrogenated at room temperature and atmospheric pressure, using 10% palladium on charcoal (2.5 g) as catalyst, until hydrogen uptake ceased. The catalyst was filtered off and evaporation to dryness gave ethyl 2-amino-4-(2-aminophenyl)butyrate used without purification for the next synthetic step.
Reaction SMILES: C(Cl)(=O)C1C(=CC(=CC=1)C(Cl)=O)C(Cl)=[O:5].[NH3:16].Cl.[C:18]([C:21]1[CH:29]=[C:28]([C:30](=[O:32])[NH2:31])[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O)(=[O:20])N>CC(C)=O>[C:23]([C:22]1[CH:26]=[CH:27][C:28]([C:30](=[O:32])[NH2:31])=[CH:29][C:21]=1[C:18]([OH:20])=[O:5])(=[O:25])[NH2:16]
Reactant: N
Reactant: NC(=O)c1ccc(C(=O)O)c(C(N)=O)c1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)c(C(=O)Cl)c1
Agent: Cl
Solvent: CC(C)=O
Product: NC(=O)c1ccc(C(N)=O)c(C(=O)O)c1
Yield: 89 %

Procedure:
A solution of 21.1 g (0.10 mol) of trimellitoyl chloride in 25 ml of acetone was dropped into 200 ml of 29% aqueous ammonia, while the aqueous ammonia was stirred under cooling with ice. The resulting mixture was as such stirred for one hour, deaerated in a vacuum and acidified with concentrated hydrochloric acid under cooling with ice. The crystals thus precipitated were recovered by filtration, washed with water and dried with hot air to give 18.5 g of a mixture of 2,4-dicarbamoylbenzoic acid and 2,5-dicarbamoylbenzoic acid as a white crystal (yield: 89%).
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:33](Cl)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:2]([NH:1][C:33]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (614 mg, 91%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:13]=1)=[O:4].[OH-].[K+].O>C(O)C>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:3]([OH:4])=[O:2])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccsc1COc1ccc(CCCCO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccsc1COc1ccc(CCCCO)cc1
Yield: 87 %

Procedure:
A stirred solution of 7.96 g of 2-[4-(4-hydroxybutyl)phenoxymethyl]-3-thiophenecarboxylic acid methyl ester, 14.41 g of potassium hydroxide, 15 ml of water and 100 ml of 95% ethanol was refluxed for one hour. The solution was concentrated. The residue was diluted with 200 ml of water and the solution was extracted once with ether. The aqueous phase was acidified with concentrated hydrochloric acid, with cooling, and the precipitate was collected, washed with water and dried in vacuo at 40° C. overnight over sodium hydroxide pellets. Recrystallization from 20 ml of 95% ethanol gave 6.62 g (88%) of product, m.p. 139.5°-141° C.
Reaction SMILES: C(S([NH:7][C@@:8]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)([CH3:18])[CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13])=O)(C)(C)C.Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>CO>[F:26][C:21]1[CH:20]=[C:19]([C@@:8]2([CH3:18])[NH:7][C:12](=[O:13])[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9]2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: COC(=O)C(C)(C)CC[C@](C)(NS(=O)C(C)(C)C)c1cc(F)cc(F)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(C)CC[C@@](C)(c2cc(F)cc(F)c2)NC1=O
Temperature: 110 °C

Procedure:
To a solution of methyl (5S)-5-[(tert-butylsulfinyl)amino]-5-(3,5-difluorophenyl)-2,2-dimethylhexanoate (1.14 g, 2.93 mmol) in MeOH (60 mL), cooled to 0° C., was added anhydrous HCl gas for 1 minute. The reaction was sealed and allowed to sit at 0° C. for fifteen minutes at which point the reaction was complete by LCMS analysis. Nitrogen was bubbled through the reaction for twenty minutes. The reaction was concentrated in vacuo. Additional MeOH (50 mL) was added and it was again concentrated in vacuo. This was repeated with another addition of MeOH and triethylamine (1.18 g, 11.7 mmol). To the resulting residue was added toluene (50 mL) and triethylamine (1.18 g, 11.7 mmol). A reflux condenser was attached and the mixture stirred at 110° C. After five days of stirring at reflux, the reaction was judged to be complete by LCMS. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with diethyl ether (75 mL) and washed individually with 30 mL of each of the following aqueous solutions: 1M HCl (twice), water, saturated brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2—1:99 to 5.5:94.5, to give the title compound. MS: m/z=254 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[C:6]([N:8]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]([CH3:28])([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:22])=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[C:12]([C:29]([CH3:36])([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:30])[CH:13]=3)[CH:7]=1.[Li]CCCC.C([O:52][B:53](OC(C)C)[O:54]C(C)C)(C)C>C1COCC1.CCCCCC>[CH3:28][C:21]([C:17]1[CH:18]=[CH:19][C:20]2[N:8]([C:6]3[C:5]([O:37][CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][O:39]4)=[C:4]([B:53]([OH:54])[OH:52])[CH:3]=[C:2]([CH3:1])[CH:7]=3)[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([C:29]([CH3:30])([CH2:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:36])=[CH:11][CH:10]=3)([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH3:22]
Reactant: Cc1ccc(OC2CCCCO2)c(-n2c3ccc(C(C)(C)CC(C)(C)C)cc3c3cc(C(C)(C)CC(C)(C)C)ccc32)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)c(OC2CCCCO2)c(-n2c3ccc(C(C)(C)CC(C)(C)C)cc3c3cc(C(C)(C)CC(C)(C)C)ccc32)c1
Reaction time: 3 h
Yield: 78.1 %

Procedure:
The 9-(5-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-3,6-bis(2,4,4-trimethylpentan-2-yl)-9H-carbazole (5.00 g, 8.6 mmol) is dissolved in 50 mL THF in a 250 mL round bottom flask in an ice water bath. n-BuLi (7.0 ml of a 1.6 M solution in hexane, 11.2 mmol) is added dropwise via syringe (soln turns yellow in color) and the brown solution stirred for 3 hours. Triisopropylborate (2.37 mL, 11.2 mmol) is added dropwise via syringe and the solution stirred for one hour, during which time the mixture became turbid and darkened in color. The mixture is quenched with 100 mL ice water. The solution is extracted with 2×100 mL Et2O. The combined organic portions are dried with MgSO4, filtered and rotovapped down to a white solid (5.1 g). This solid is added to 200 mL water and stirred for 1.5 hrs. The mixture is extracted with 150 and 100 mL Et2O. The combined organic extract is dried with MgSO4, filtered and rotovapped down to yield 4.2 g (78% yield) of a white powder. 1H NMR (CDCl3): δ 8.07 (d, JH—H=1.4 Hz, 1H, CBZ), 8.04 (d, JH—H=1.4 Hz, 1H, CBZ), 7.69 (d, JH—H=2.3 Hz, 1H, aryl), 7.42 (dd, JH—H=8.6, 1.8 Hz, 2H, CBZ), 7.40 (dd, JH—H=8.6, 1.7 Hz, 1H, CBZ), 7.37 (d, JH—H=2.3 Hz, 1H, aryl), 7.18 (d, JH—H=8.6 Hz, 1H, CBZ), 6.99 (d, JH—H=8.6 Hz, 1H, CBZ), 6.34 (s, 2H, OH), 3.80 (m, 2H, THP), 2.91 (m, 1H, THP), 2.39 (s, 3H, aryl Me), 1.89 (dd, JH—H=12.8, 4.2 Hz, 2H, tOCT CH2), 1.82 (d, JH—H=14.5 Hz, 2H, tOCT CH2), 1.55 (s, 3H, tOCT CMe2), 1.52 (s, 3H, tOCT CMe2), 1.48 (s, 3H, tOCT CMe2), 1.45 (s, 3H, tOCT CMe2), 0.71 (s, 9H, tOCT tBu), 0.70 (s, 9H, tOCT tBu).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)[CH3:2].[C-:13]#[N:14].[K+]>[Cu]C#N>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:13]#[N:14])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)Cl)cc1
Reactant: [C-]#N
Agent: N#C[Cu]
Agent: [K+]
Product: CCOc1ccc(C(=O)C#N)cc1
Yield: 94.5 %

Procedure:
In the manner described above, 184 g (1 mol) of p-ethoxybenzoyl chloride, 62.5 g (0.96 mol) of potassium cyanide and 3.6 g (0.04 mol) of copper(I) cyanide were reacted with one another at 215° C. After working up, 159 g (91% of theory) of p-ethoxybenzoyl cyanide were obtained; melting point 43° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:19][C:20](=[O:33])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>ClCCCl.O>[CH2:12]([O:19][C:20](=[O:33])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: Nc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.7 %

Procedure:
A solution of N-tert-butoxycarbonylaminoacetaldehyde (0.28 g, 1.76 mmol) in 1,2-dichloroethane (DCE, 5 mL) was added to a solution of [4-(4-aminophenyl)butyl]carbamic acid benzyl ester (0.48 g, 1.6 mmol) in DCE (10 mL) and acetic acid (0.108 mL, 1.6 mmol). The mixture was stirred at room temperature for 20 min. NaB(OAc)3H (0.48 g, 2.26 mmol) was then added into the mixture which was further stirred at room temperature overnight. Water (10 mL) was added and the mixture was acidified to pH 7 by 10% aqueous HCl. The organic fraction was isolated and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, ethyl acetate/hexane, 1:2, v/v) to afford the protected diamine 600 (0.33 g, 47%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.54 (m, 2H), 2.51 (m, 2), 3.18 (m, 4H), 3.36 (m, 2H), 3.89 (br s, 1H), 4.69 (br s, 1H), 4.78 (br s, 1H), 5.51 (s, 2H), 6.54 (d, 2), 6.96 (d, 2H), 7.33 (m, 5H). m/z (ESI) 442 [C25H35N3O4+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:41]([N:51]([CH2:53][C:54](O)=[O:55])[CH3:52])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:44]([O:43][C:41]([N:51]([CH3:52])[CH2:53][C:54]([O:33][C@H:31]([CH3:32])[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22](=[O:23])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:25](=[O:40])[N:26]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:55])=[O:42])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN(C)C(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a mixture of (R)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.68 mmol), N-Cbz-sarcosine (1.643 g, 7.36 mmol) and DMAP (0.9 g, 7.36 mmol, Aladdin) in 15 mL of CH2Cl2 was added EDC solid (1.06 g, 5.52 mmol, Aladdin) in portions at 0° C. After stirring at 0° C. for 2 hrs, the reaction mixture was warmed up to room temperature, and continued to stir at rt overnight. The mixture was diluted with 100 mL of CH2Cl2 and the resulted solution was washed with 0.1 N HCl (10 mL×2), followed by saturated NaHCO3 solution (20 mL×2) and water (20 mL). The aqueous phase was extracted with EtOAc (50 mL×3), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/hexane=2/1) to give the desired compound as a pale yellow solid (2.31 g, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24](OB(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])[CH3:20].ClCCl>C(N(CC)CC)C>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH3:20]
Reactant: CCCOCCOc1ccc(OB(O)O)cc1OCC
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1OCC
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g), 3-ethoxy-4-(2-propoxyethoxy)phenylboric acid (0.80 g), cupric acetate (0.27 g), MS4A (0.8 g) and dichloromethane (15 ml) was added at room temperature triethylamine (1.04 ml), and the resulting mixture was stirred for 16 hours. The reaction mixture was filtered to remove an insoluble material and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:2→2:3) to obtain methyl 7-[3-ethoxy-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.45 g) as a light yellow, oily substance. 1H-NMR (200 MHz, CDCl3) δ0.95 (3H, t, J=7.4 Hz), 1.44 (3H, t, J=7.0 Hz), 1.56-1.70 (2H, m), 3.04-3.11 (2H, m), 3.53 (2H, t, J=6.8 Hz), 3.58-3.65 (2H, m), 3.80-3.85 (5H, m), 4.03 (2H, q, j=7.0 Hz), 4.17-4.22 (2H, m), 6.56-6.63 (2H, m), 6.94-7.04 (3H, m), 7.70 (1H, s), 8.08 (1H, d, J=8.4 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:9]=1[C:10](O)=[O:11].CN(C=O)C>C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OCc1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Oxalyl chloride (13.0 mL) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid in CH2Cl2 (200 mL). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 h. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 mL). The resulting solution is cooled in an ice-bath and LiBH4 (3.4 g) is added in portions. The cooling bath is removed and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with THF and treated with 0.1 M hydrochloric acid. Then, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried (Na2SO4) and the solvent is evaporated under reduced pressure to give the crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14](=[O:33])[CH2:15][C:16]2[C:30]([CH3:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:17]=2[C:18]([N:20]=[S:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:6]=1.OO.C(=O)([O-])[O-:37].[Na+].[Na+].C(Cl)Cl>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:14](=[O:33])[CH2:15][C:16]2[C:30]([CH3:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:17]=2[C:18]([N:20]=[S:21]2(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:19])[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:6]=1
Reactant: Cc1cc(Cl)cc(C(=O)N=S2CCCCC2)c1CC(=O)c1cc(Br)nn1-c1ccccc1Cl
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(Cl)cc(C(=O)N=S2(=O)CCCCC2)c1CC(=O)c1cc(Br)nn1-c1ccccc1Cl
Reaction time: 18 h

Procedure:
0.2 g 2-{2-[5-Bromo-2-(2-chloro-phenyl)-2H-pyrazol-3-yl]-2-oxo-ethyl}-5-chloro-3-methyl-N-(tetrahydro-1lambda*4*-thiopyran-1-ylidene)-benzamide (0.35 mmol) were dissolved in 10 ml acetic acid. 4 mg Sodium wolframate dihydrate were added. 45 mg of a 30% solution of hydrogenperoxide was added dropwise and the resulting solution was stirred for 18 h. The reaction mixture was poured into a saturated aqueous sodium carbonate solution, methylene chloride was added and the organic pase was subsequently washed with water and saturated aqueous sodium carbonate. The organic solvent was dried and the solvent removed. Column chromatography yielded 0.07 g of the desired product, compound I.4-22.