Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C[N:19](C)[C:20]#[N:21].C1C(O)=CC=CC=1C.Cl>>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[C:2]([NH:1][C:20]([NH2:21])=[NH:19])[CH:7]=1)=[O:9]
Reactant: COC(=O)c1ccc(N2CCOCC2)c(N)c1
Reactant: CN(C)C#N
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: COC(=O)c1ccc(N2CCOCC2)c(NC(=N)N)c1

Procedure:
A mixture of 4-(2-amino-4-methoxycarbonylphenyl)morpholine (2.7 g), N,N-dimethyl cyanamide (1 g) and m-cresol (15 ml) was heated at 90°-95° C. for 10 hours. Ice was added and the reaction mixture acidified to pH 4 by the addition of 2N hydrochloric acid and the resultant mixture extracted with ether. The aqueous layer was cooled, basified to pH 8 by the addition of solid sodium bicarbonate and then extracted with dichloromethane. The extract was dried and the solvent removed to yield an oily residue which was purified by chromatography on a neutral alumina column eluted with a 1:99 mixture of methanol and dichloromethane to give 1,1-dimethyl-2-(5-methoxycarbonyl-2-morpholinophenylguanidine (m.p. 152°-154° C.).
Reaction SMILES: I[C@@H:2]1[C@@H:8]2[CH2:9][C@@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[OH-].[Na+].[CH2:13]([OH:15])[CH3:14]>>[O:15]1[C@H:2]2[C@@H:13]1[CH2:14][C@@H:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH2:4][CH2:3]2
Reactant: O=C1O[C@H]2C[C@@H]1CC[C@@H]2I
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)[C@H]1CC[C@H]2O[C@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1S,4S,5S)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-on (J. Org. Chem., 1996, Vol. 61, p. 8687) (89.3 g) was dissolved in ethanol (810 ml), a 2N aqueous solution (213 ml) of sodium hydroxide was added, and the mixture was then stirred at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, and water was added to the residue to conduct extraction with dichloromethane, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=17:3) to obtain the title compound (41.2 g) as a pale yellow oil.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH:25](O)(C)[CH3:26]>>[C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:25][CH3:26].[C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(C)O
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Temperature: 30 °C

Procedure:
Behenic acid manufactured by Henkel Co. (trade name: Edenor C22-85R) in an amount of 100 kg was admixed with 1200 kg of isopropyl alcohol, and dissolved at 50° C. The mixture was filtrated through a 10 μm filter, and cooled to 30° C. to allow recrystallization. Cooling speed for the recrystallization was controlled to be 3° C./hour. The resulting crystal was subjected to centrifugal filtration, and washing was performed with 100 kg of isopropyl alcohol. Thereafter, the crystal was dried. The resulting crystal was esterified, and subjected to GC-FID analysis to give the results of the content of behenic acid being 96 mol %, lignoceric acid 2 mol %, and arachidic acid 2 mol %. In addition, erucic acid was included at 0.001 mol %.
Reaction SMILES: CN1CCOCC1.CN(C1C=CC=CN=1)C.[C:17]([NH:21][C:22]([C:24]1[O:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=1[C:32]([OH:34])=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCl.C(OCC)(=O)C>[C:17]([N:21]1[C:22](=[O:23])[C:24]2[O:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=2[C:32]1=[O:34])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)c1noc(C(=O)NC(C)(C)C)c1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)c1noc2c1C(=O)N(C(C)(C)C)C2=O
Yield: 86.8 %

Procedure:
7.5 g (74.1 mmol) of methylmorpholine, 2.4 g (20 mmol) of dimethylaminopyridine and 17.4 g of a 50% strength solution of propanephosphonic anhydride (27.3 mmol) in dichloromethane were add dropwise in succession to 5.1 g (20 mmol) of 5-tert-butylaminocarbonyl-3-isopropylisoxazole-4-carboxylic acid in 200 ml of dichloromethane at -5° C., and the mixture was then refluxed for 6 hours. The solvent was stripped off under reduced pressure, the residue was taken up in 300 ml of ethyl acetate and the solution was extracted twice with saturated sodium bicarbonate solution and once each with 5% strength citric acid solution, saturated sodium carbonate solution and saturated sodium chloride solution. The organic phase was dried and the solvent was stripped off under reduced pressure. 4.1 g (87%) of N-tert-butyl-3-isopropylisoxazole-4,5-dicarboximide were obtained as a solid of melting point 60°-62° C. (Example No. 1.003).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][C:11]#[CH:12])=[O:7])([CH3:4])[CH3:3].[CH:16]1(O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]#[CH:12])[C:13]([O:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:14])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: OC1CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of Boc-L-propargyl glycine (5 g, 23.45 mmol) in DCM (100 ml) was added cyclopentanol (3.03 g, 35.2 mmol), EDC (4.93 g, 25.8 mmol) and DMAP (0.286 g, 2.345 mmol). The mixture was stirred overnight at RT. The solvent was removed under reduced pressure and the residue was subjected to column chromatography eluting with 7 to 12% EtOAc in hexanes. Yield=5.5 g, 19.55 mmol, 83% yield.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]([C:11]1[C:16]([NH2:17])=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:7][O:8][C:9]([C:11]1[C:16]([NH:17][C:24](=[O:25])[C:23]2[CH:27]=[C:19]([Br:18])[CH:20]=[CH:21][C:22]=2[F:28])=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10]
Reactant: COC(=O)c1nccnc1N
Reactant: O=C(Cl)c1cc(Br)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1nccnc1NC(=O)c1cc(Br)ccc1F
Temperature: 40 °C
Yield: 74.9 %

Procedure:
Pyridine (7.75 g, 98.0 mmol) was added at 0° C. under N2 to a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester 101 (1.5 g, 9.80 mmol) and 5-bromo-2-fluorobenzoylchloride (9.45 g, 49.0 mmol) in CH2Cl2. The reaction mixture was warmed at 40° C. for 4 h, then cooled down at room temperature. The reaction mixture was quenched with 20 mL of ethanol, evaporated, partitioned between CH2Cl2 and 1N NaHCO3, dried (Na2SO4) and evaporated. The crude material was triturated in EtOH, filtered, washed with EtOH and ether to give 2.6 g of 3-(5-bromo-2-fluorobenzoyl-amino)pyrazine-2-carboxylic acid methyl ester 102 as a white powder (LCMS analysis).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=1)([O-])=O.O.O.[Sn](Cl)[Cl:22].O.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[ClH:22].[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=1
Reactant: Cl[Sn]Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cl
Product: Nc1ccc(C(=O)O)c(-c2ccccc2)c1
Yield: 29.7 %

Procedure:
4-Nitro-2-phenylbenzoic acid (10.5 g, 43.2 mmol) and tin(II) chloride dihydrate (34.1 g, 0.15 mol) were combined and refluxed in 250 mL ethyl acetate for 1 hour. An equal volume of water was added followed by solid NaHCO3 to pH 8. The mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine and concentrated to a thick oil. The oil was diluted with ether and excess anhydrous HCl was added. The resulting precipitate was collected and dried to provide 4-Amino-2-phenylbenzoic acid hydrochloride (3.2 g). MS m/e 214 (M+H)+. 1H NMR (d6-DMSO, 300 MHz) δ 6.65 (d, J=3 Hz, 1H), 6.79 (m, 1H), 7.20-7.72 (m, 6H).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:10]O)[C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5].S(Cl)(Cl)=O.[C:16](Cl)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([NH:2][C@@H:3]([CH2:10][Cl:1])[C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5])(=[O:18])[CH3:17]
Reactant: CCCOC(=O)[C@@H](N)CO
Reactant: CC(=O)Cl
Reactant: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCOC(=O)[C@H](CCl)NC(C)=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
(S)-Propyl 2-amino-3-hydroxypropanoate HCl salt (18.2 g, 99.1 mmol) was suspended in toluene (96 mL) and then thionyl chloride (8.20 mL, 13.3 g, 112 mmol) was added via an addition funnel during 15 min. The homogeneous reaction was stirred at 20° C. for 2 h. Then, the temperature was raised to 60° C. during 45 min and the reaction was maintained at that temperature for 45 min. Then, acetyl chloride (15.1 mL, 16.7 g, 213 mmol) was added via an addition funnel during a period of 2 h while the temperature reached 80° C. and the reaction was further stirred at that temperature for 30 min. The reaction was allowed to cool to 5° C. while a precipitate formed. The precipitate was collected on a fritted funnel under suction and washed with petroleum benzene (3×25 mL). The cake was dried under vacuum overnight to a final weight of 9.19 g. The mother liquor was seeded with some crystals of the cake and further diluted with petroleum benzene (25 mL) and stirred overnight at 20° C. The ensuing suspension was cooled to 5° C. and the product was collected on a fritted funnel under suction and washed with petroleum benzene (3×25 mL). The cake was dried under vacuum overnight to a final weight of 6.48 g. Combined weight (two cakes) 15.7 g, approx. 76% yield. 1H NMR: (CDCl3, 300 MHz): δ 6.40 (br s, 1H), 4.99 (dt, 1H), 4.27-4.11 (m, 2H), 3.95 (dq, 2H), 2.09 (s, 3H), 1.77-1.65 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:26][NH2:27])[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[S:29]1[CH:33]=[C:32]([CH:34]=O)[N:31]=[CH:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:28])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:26][NH:27][CH2:34][C:32]2[N:31]=[CH:30][S:29][CH:33]=2)[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CN)n2)c(OC)c1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CNCc3cscn3)n2)c(OC)c1
Reaction time: 16 h
Yield: 29.4 %

Procedure:
To a solution of (5-amino-6-aminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (Example 20, product from Step 3) (422 mg, 1.1 mmol, 1 equiv), 1,3-thiazole-4-carbaldehyde (150 mg, 1.3 mmol, 1.2 equiv.) and acetic acid (32 μL, 2.2 mmol, 2 equiv) in DCE (5 mL) was added sodium triacetoxyborohydride (400 mg, 1.87 mmol, 1.7 equiv) and the reaction mixture was stirred for 16 h. Saturated NaHCO3 was added and the product was extracted with dichloromethane. The organic phase was dried (MgSO4), filtered and the solvent evaporated. The crude material was purified by column chromatography (SiO2, eluted with dichloromethane—MeOH/NH3 0-10%) to afford (5-amino-6-{[(thiazol-4-ylmethyl)-amino]-methyl}-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (157 mg). MS: [M+H]+=486.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:41])([F:40])[C:13]1[CH:14]=[C:15]([C@H:23]([O:25][C@H:26]2[CH2:30][CH2:29][C@@H:28]([CH2:31][OH:32])[C@@H:27]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH3:24])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[C:15]([C@H:23]([O:25][C@H:26]2[CH2:30][CH2:29][C@@H:28]([CH:31]=[O:32])[C@@H:27]2[C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH3:24])[CH:14]=[C:13]([C:12]([F:41])([F:11])[F:40])[CH:18]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](CO)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@@H](O[C@H]1CC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -70 °C
Reaction time: 0.21 h
Yield: 88.5 %

Procedure:
To a solution of 5.4 mL (61.7 mmole) of oxalyl chloride in 100 mL of methylene chloride cooled to −70° C. was added dropwise 8.7 mL (123 mmole) of DMSO. The reaction was stirred for 10-15 minutes at −70° C. and then a solution of 11.11 g (24.7 mmole) of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(hydroxymethyl)cyclopentane, prepared as in Example 19, Step A, in 40 mL of methylene chloride was added dropwise at −70° C. The reaction was stirred for 1 hour before dropwise addition of 43 mL (246 mmole) of DIPEA in 25 mL of methylene chloride. After 5 minutes, the dry ice/acetone bath was removed and the reaction was warmed to room temperature in a water bath and stirred for 1 hour. The reaction was then diluted with methylene chloride and water containing 150 mL of 2N hydrochloric acid and the layers were separated. The aqueous layer was reextracted with methylene chloride and the organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and evaporated. The residue was purified by FC (10% ethyl acetate/hexanes) to give 9.8 g of title compound as a waxy solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O>C(#N)C.S(=O)(O)[O-].[Na+].CCOCC.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)c1ccc(Br)cc1CBr
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid methyl ester (115 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 mL) was warmed over 45 minutes to a gentle reflux, and held at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite, and concentrated in vacuo. The residue was partitioned between water and 1:1 hexanes:ethyl acetate. The organic phase was washed with water, brine, and filtered through a pad of silica gel. The solvent was removed under vacuum to give an oil/solid mixture, which was digested in ether and filtered. The filtrate was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting the product at 4:1 hexanes-ethyl acetate and providing 102 g of 4-bromo-2-bromomethyl-benzoic acid methyl ester, in 66% yield; 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([F:17])[CH:5]=[CH:4][C:3]=1[NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20].I[C:26]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][C@@H:39]([NH:41][C:42](=[O:45])[O:43][CH3:44])[CH3:40])[N:32]=2)=[CH:29][N:28]([CH:46]([CH3:48])[CH3:47])[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[F:1][C:2]1[C:3]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:20])=[O:21])=[CH:4][CH:5]=[C:6]([F:17])[C:7]=1[C:26]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH2:38][C@@H:39]([NH:41][C:42](=[O:45])[O:43][CH3:44])[CH3:40])[N:32]=2)=[CH:29][N:28]([CH:46]([CH3:48])[CH3:47])[N:27]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: COC(=O)N[C@@H](C)CNc1nccc(-c2cn(C(C)C)nc2I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCS(=O)(=O)Nc1ccc(F)c(-c2nn(C(C)C)cc2-c2ccnc(NC[C@H](C)NC(=O)OC)n2)c1F
Temperature: 80 °C

Procedure:
A mixture of crude Intermediate N-(2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide (854 mg), Intermediate (S)-methyl 1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (350 mg, 90% pure), tetrakis(triphenylphosphine)palladium(0) (90 mg), 2 M aqueous sodium carbonate solution (6 ml), toluene (50 ml), and ethanol (6 ml) was heated at 80° C. for 16 h. The cooled mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (70:1 to 40:1 DCM/methanol eluant) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.[F:37][CH2:38][CH2:39][NH2:40].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:40][CH2:39][CH2:38][F:37])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: NCCF
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCCF)c(F)c3)c2cc1OC
Yield: 145.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in toluene (10 ml) and triethylamine (0.5 ml) with heating. A solution of triphosgene (47 mg) in dichloromethane (1.0 ml) was then added to the solution, and the mixture was heated under reflux for 5 min. Next, 2-fluoroethylamine hydrochloride (42 mg) was added thereto, and the mixture was heated under reflux for additional 8 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to give 93 mg (yield 72%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:16](=O)(O)[O-:17].[K+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C(Cl)Cl.O>[CH2:1]([N:15]=[C:16]=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C([O-])O
Reactant: CCCCCCCCCCCCCCN
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN=C=O
Reaction time: 0.5 h

Procedure:
To a vigorously-stirred, biphasic mixture of 1-tetradecylamine (9.44 g, 44.2 mmol) in CH2Cl2 (300 mL) and potassium bicarbonate (21.8 g, 158 mmol) in H2O (200 mL) was added (dropwise) a 1.93 M solution of phosgene in toluene (30.0 mL, 57.9 mmol) at 0° C. After 30 min, the organic layer was separated and dried over MgSO4. The volatile components were removed with a rotary evaporator to afford crude tetradecyl isocyanate which was immediately taken up in THF (15 mL) and added to a heterogeneous mixture of 5,6-dichlorobenzotriazole (5.94 g, 31.6 mmol) and THF (125 mL). The reaction mixture was stirred at ambient temperature for 14 h, and the volatile components were then removed with a rotary evaporator. The crude product was first purified by silica gel column chromatography (heptane:ethyl acetate=7:3) and then recrystallized from ethanol to afford 12.2 g (90%) of D12.
Reaction SMILES: [CH2:1]([O:8][C:9](=S)[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:23]([NH:26][NH2:27])([CH3:25])[CH3:24].C(N(CC)CC)C.O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:26]([CH:23]([CH3:25])[CH3:24])[N:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NN
Reactant: COc1ccc(C(=O)CC(=S)OCc2ccccc2)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(OCc3ccccc3)nn2C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a suspension of 3-(4-methoxyphenyl)-3-oxothio-propionic acid O-benzyl ester (0.60 g) and isopropylhydrazine hydrochloride (0.29 g) in acetonitrile (2 mL) was added triethylamine (0.81 g) and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The solvent of the organic layer was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: hexane/dichloromethane=3/1-1/3) to give the title compound (0.40 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([OH:16])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[Cl:20][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([Cl:10])[CH:19]=1)[C:14]([N:63]1[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])[CH2:65][CH2:64]1)=[O:16]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(Cl)cc(Cl)c2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 33.8 %

Procedure:
DIPEA (149.8 mg, 0.2 mL, 1.15 mmol) was added to a stirred solution of 3,5-dichloro-benzoic acid (49.2 mg, 0.25 mmol) in DMF (3 mL). HOBT (38.2 mg, 0.28 mmol) and EDCI (123 mg, 0.34 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.30 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 42 mg (32.8% yield) of biphenyl-4-carboxylic acid {2-[4-(3,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 98.36%. 1H NMR (DMSO-d6): δ 8.7-8.62 (t, 1H), 8.0-7.94 (d, 2H), 7.84-7.7 (m, 5H), 7.58-7.46 (m, 4H), 7.44-7.36 (m, 1H), 4.26-4.1 (bs, 2H), 3.74-3.46 (bs, 7H), 3.42-3.34 (m, 1H).