Azzindani/Open_Reaction_Data huggingface dataset:
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]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[F:46][C:47]1[CH:52]=[CH:51][C:50]([C@H:53]([NH2:55])[CH3:54])=[CH:49][CH:48]=1>C(Cl)(Cl)Cl>[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:38]([NH:55][C@@H:53]([C:50]2[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=2)[CH3:54])=[O:44])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1OC
Reactant: C[C@@H](N)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccc(F)cc4)c(C(F)(F)F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-(trifluoromethyl)aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (15 mg, yield 34%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7](N1CCOCC1)C.[C:15]([NH:22][C@H:23]([C:28]([OH:30])=O)[CH2:24][CH:25]([CH3:27])[CH3:26])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C)C=O>[NH:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:23]([C:28]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:30])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CCN1CCOCC1
Reactant: NCC(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To the solution of 5.02 g of hydrochloride of the methyl ester of glycine in a mixture of 20 ml of dichloromethane and 30 ml of dimethylformamide, cooled to 0° C., there are added 5 ml of N-ethylmorpholine then the solution of 9.5 g of dry Boc-Leucine in 50 ml of dichloromethane. 9.04 g of dicyclohexylcarbodiimide, 6 g of 1-hydroxy benzotriazol and 1.5 ml of N-ethylmorpholine are then added. After 45 minutes at 0° C., the mixture is stirred for 5 hours at ambient temperature. The insoluble is filtered and washed with ethyl acetate. The filtrate is diluted with 700 ml of ethyl acetate and the organic solution is washed 3 times with an aqueous solution of sulfate and potassium bisulfate, then 3 times with a saturated sodium bicarbonate solution and finally 3 times with a saturated sodium chloride solution. The organic solution dried over sodium sulfate is concentrated in vacuo to 200 ml. 150 ml of hexane are added and the mixture is left to crystallize, drained and washed with hexane.
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40].CI>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH3:1])[C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40]
Reactant: CN(C)C=O
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4Cl)c(Cl)c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc2ncnc(Oc3ccc(N(C)C(=O)OCc4ccccc4Cl)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-chlorobenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (65 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (77 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (57 mg, yield 85%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:14](O)=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=3[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(Cl)([Cl:31])=O)C=CC=CC=1.C(=O)(O)[O-].[Na+].C>CCCCCC.C(OCC)(=O)C>[Cl:31][C:14]1[C:15]2[CH2:16][CH2:17][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9][C:10]=2[N:11]=[C:12]([C:19]([F:22])([F:21])[F:20])[N:13]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Oc1nc(C(F)(F)F)nc2c1CCN(Cc1ccccc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: FC(F)(F)c1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 150 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of 29.6-g (95.7 mmol) of 7-(phenylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (prepared essentially as described in Example 1, Step A) and 53 mL of phenylphosphonic dichloride in a 250-mL round bottom flask was heated at 150° C. After 2 h, the reaction was judged to be complete by TLC analysis. The mixture was cooled to ambient temperature and poured onto 400 g of ice, transferring with ˜500 mL of ethyl acetate. The aqueous layer was neutralized with solid sodium bicarbonate and the layers separated. The aqueous layer was extracted with two portions of ethyl acetate. The combined organics were washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated to give a brown solid. The solid was boiled in 2 L of hexane with charcoal, filtered, and concentrated in vacuo to give 23.9 g (76%) of the title compound as a yellow solid. LC-MS 328.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([N:37]1[CH2:38][CH2:39][CH:40]([NH:43][C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)=[CH:26][CH:25]=2)[CH2:41][CH2:42]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: CCOC(=O)N1CCC(NC(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-aminopiperidine-1-carboxylic acid ethyl ester as in General Procedure 10 to give the title compound. LCMS: m/z=601.99 (M+H+); retention time=0.85 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](C)[C:5](C#N)=[N:6][CH:7]=1.[OH-:11].[Na+].[CH2:13]([OH:15])[CH3:14]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:5])[C:14]([C:13]([OH:11])=[O:15])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C#N
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cnc1C(=O)O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of 5-bromo-3-methylpyridine-2-carbonitrile (3.9 g, 20 mmol) in ethanol (30 mL) was added 6.0 M sodium hydroxide in water (15 mL), and the reaction was stirred at 80° C. for 1.5 h. The reaction mixture was concentrated, diluted with water and partitioned in EtOAc. The aqueous phase was acidified to pH 2-3. The product then was extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated to give 4.2 g (98% yield) of the desired product as a yellow solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[F:28][C:29]([F:49])([F:48])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][N:36]([S:44]([CH3:47])(=[O:46])=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)=[O:31]>>[F:49][C:29]([F:28])([F:48])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][N:36]([C:37]1[CH:38]=[CH:39][C:40]([NH:43]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:41][CH:42]=1)[S:44]([CH3:47])(=[O:45])=[O:46])=[O:31]
Reactant: CS(=O)(=O)N(CCCNC(=O)C(F)(F)F)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCCNC(=O)C(F)(F)F)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(3-trifluoroacetylamino-propyl)-N-methylsulphonyl-p-phenylenediamine Rf value: 0.5 (aluminium oxide, methylene chloride/methanol=20:1) C29H27F3N4O6S
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[N:20]1([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH:30]([C:34](O)=[O:35])[CH2:29][CH2:28]3)[CH:24]=[N:23][N:22]=[N:21]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClC(Cl)C>[O:1]=[C:2]1[CH2:7][N:6]([C:34]([CH:30]2[C:31]3[C:27](=[CH:26][C:25]([N:20]4[CH:24]=[N:23][N:22]=[N:21]4)=[CH:33][CH:32]=3)[CH2:28][CH2:29]2)=[O:35])[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Reactant: O=C(O)C1CCc2cc(-n3cnnn3)ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: N#Cc1ccc2c(c1)CCC(N1CCN(C(=O)C3CCc4cc(-n5cnnn5)ccc43)CC1=O)C2

Procedure:
A mixture of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (40 mg, 0.16 mmol) (20 mg, 0.078 mmol), 5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylic acid (18 mg, 0.078 mmol), DMAP (14 mg, 0.12 mmol), and EDC (23 mg, 0.12 mmol) was stirred in dichloroethane (2 mL) for 2 hours. The solvent was removed under vacuum, and the residue was redissolved in methanol, and purified by reverse phase HPLC to give the title product. LC-MS (IE, m/z): 468 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:14][CH2:13][Br:12])[CH:5]=1
Reactant: BrCCBr
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCCBr)c1
Temperature: 25 °C

Procedure:
A flask is charged with 3-hydroxybenzoic acid methyl ester (2.54 g, 16.0 mmol) and acetone (50 mL). 1,2-Dibromo-ethane (5.69 mL, 66.0 mmol) and potassium carbonate (2.76 g, 19.0 mmol) are added and the mixture is refluxed for 24 h. The reaction mixture is then cooled to room temperature. The solids are filtered off and the filtrate concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 3:1) to afford 3-(2-bromo-ethoxy)-benzoic acid methyl ester as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.66 (t, J=6.2 Hz, 2H), 3.93 (s, 3H), 4.35 (t, J=6.2 Hz, 2H), 7.14 (m, 1H) 7.37 (m, 1H) 7.57 (m, 1H) 7.68 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1.[Cl:18][C:19]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:21]2[C:22]([O:24][C:25](=[O:26])[C:20]=12)=[O:23]>>[NH2:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:22]([C:21]3[C:27]([Cl:30])=[CH:28][CH:29]=[C:19]([Cl:18])[C:20]=3[C:25]([OH:26])=[O:24])=[O:23])=[CH:15][CH:16]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1
Reactant: CCCc1nc(N)sc1Cc1ccc(N)cc1
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Product: CCCc1nc(N)sc1Cc1ccc(NC(=O)c2c(Cl)ccc(Cl)c2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.9 %

Procedure:
1.9 g of 2-amino-5-(4-aminobenzyl)-4-propylthiazole (7.65 mmol) and 1.7 g of 3,6-dichlorophthalic anhydride are reacted under the conditions of Example 26. The reaction mixture is stirred for one day at room temperature. After concentration, a beige solid is obtained which is triturated in ether to give 2.2 g of 2-[4-(2-amino-4-propylthiazol-5-ylmethyl)phenylaminocarbonyl]-3,6-dichlorobenzoic acid in the form of a beige powder melting at 153° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[C:14]([O-:24])(=[O:23])[C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16].O[C@@H](C1C=CC=CC=1)C(O)=O>C(OCC)(=O)C>[OH:16][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([O-:24])=[O:23].[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:7]2[CH2:13][C@@H:10]([CH2:9][CH2:8]2)[C@@H:11]1[NH3+:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: O=C(O)[C@@H](O)c1ccccc1
Agent: O=C([O-])[C@@H](O)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1[NH3+]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
In order to determine the enantiomeric excess, (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester was derivatized to the (S)-mandelate salt as follows: To a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (34.2 mg, 0.187 mmol) in ethyl acetate (1 mL) was added (S)-α-hydroxyphenylacetic acid (28.7 mg, 0.187 mmol) and the mixture was stirred at 25° C. for 0.5 h. The solid was filtered and dried under high vacuum to afford (1R,2S,3R,4S)-3-ethoxycarbonyl-bicyclo[2.2.1]hept-2-yl-aminium (S)-α-hydroxyphenylacetate (11.4 mg, 0.034 mmol, 18%, de=97%), as a white solid. 1H NMR (400 MHz, CDCl3) 1.08-1.20 (3H, m), 1.28 (3H, t, J=7.1 Hz), 1.50-1.59 (2H, m), 1.79 (1H, d, J=10.9 Hz), 2.23 (1H, s), 2.46-2.48 (2H, m), 3.04 (1H, d, J=7.8 Hz), 4.05-4.18 (2H, m), 4.89 (1H, s), 5.49 (3H, bs), 7.22-7.31 (3H, m), 7.43 (2H, d, J=6.9 Hz).
Reaction SMILES: NC1C=CC([NH:8][C:9]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=CC=1.C1(CCCC(O)=[O:30])C=CC=CC=1.O.[OH:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[N+:34]([C:38]1[CH:37]=[CH:42][C:41]([NH:8][C:9]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:10])=[CH:40][CH:39]=1)([O-:33])=[O:30]
Reactant: Nc1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)CCCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2C1
Reaction time: 8 h

Procedure:
A solution of N-(4-aminophenyl)isoindoline-2-carboxamide (100 mg, 0.395 mmol), 4-phenylbutanoic acid (78 mg, 0.474 mmol), 1-hydroxybenzotriazole hydrate (66.5 mg, 0.434 mmol) and N-methylmorpholine (0.109 ml, 0.987 mmol) in N,N-dimethylformamide (1.771 ml) at room temperature was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (136 mg, 0.711 mmol). The mixture was stirred overnight and diluted with water (10 ml); the resulting suspension was filtered with water washes to give after drying product with an impurity. This solid was suspended in 2% methanol/dichloromethane and filtered to provide the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:30])=[C:11]([CH:28]=[O:29])[C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:30])=[C:11]([CH2:28][OH:29])[C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1c(CO)c2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 97 %

Procedure:
Using (−)-N-(tert-butyl)-N′-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea obtained in Example 48, the title compound was synthesized in the same manner as in Example 21. Yield: 97%. Melting point: 187-188° C. (ethyl acetate-hexane). [α]D20+34.0° (c=0.43, chloroform).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:26])[NH:5][C:6]1[N:11]=[CH:10][C:9](B(O)O)=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:19]=2)[CH:7]=1)[CH3:2].Br[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][N:37]=1)[N:34]([CH2:38][C:39]1[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=1)[CH:33]=[C:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:31]2=[O:50].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH2:1]([NH:3][C:4](=[O:26])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][N:37]=2)[N:34]([CH2:38][C:39]2[N:40]=[CH:41][N:42]([CH3:44])[CH:43]=2)[CH:33]=[C:32]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:31]3=[O:50])=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:19]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2cn(C)cn2)c2cnc(Br)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(B(O)O)cn1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(-c2cc3c(=O)c(C(=O)OCC)cn(Cc4cn(C)cn4)c3cn2)cn1
Temperature: 90 °C
Yield: 26.1 %

Procedure:
In a microwave vessel, 6-(3-ethylureido)-4-(4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 98, 0.2 g, 0.54 mmol), ethyl 6-bromo-1-((1-methyl-1H-imidazol-4-yl)methyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (Intermediate 102, 0.21 g, 0.54 mmol) and cesium carbonate (0.229 g, 0.70 mmol) were combined and suspended in a mixture of dioxane and water (5:1; 2.5 mL/0.5 mL). The suspension was degassed and purged with nitrogen. Pd(PPh3)4 (0.05 g, 0.04 mmol) was added and the mixture was degassed and purged a second time. The reaction mixture was heated in the microwave at 90° C. for 90 minutes. The reaction was partitioned between water and ethyl acetate, the layers were separated, and the organic phase was washed with saturated NaHCO3, water and brine, then dried over magnesium sulfate, and concentrated. The resulting solids were filtered, washed with acetonitrile followed by chloroform. Isolation gave 90 mg of the title compound as an off-white solid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]2[O:6][C:7]([CH3:9])=[CH:8][C:4]=2[CH:3]=1.N12CCCN=C1CCCCC2.[CH2:23]([OH:26])[C:24]#[CH:25].Cl>O1CCCC1.[Cu]I.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.O>[CH3:9][C:7]1[O:6][C:5]2[CH:10]=[CH:11][C:2]([C:25]#[C:24][CH2:23][OH:26])=[CH:3][C:4]=2[CH:8]=1
Reactant: Cc1cc2cc(I)ccc2o1
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2cc(C#CCO)ccc2o1
Temperature: 0 °C

Procedure:
A solution of 5-iodo-2-methylbenzo[b]furan (12.1 g, 46.9 mmol) in dry tetrahydrofuran (50 mL) was degassed and copper(I)iodide (280 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium (1.7 g, 1.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (9.1 g, 60.0 mmol) were added. The reaction solution was degassed again and propargyl alcohol (3.4 g, 60.7 mmol) was added under inert atmosphere at ambient temperature. The reaction mixture was stirred (initially under cooling with ice water) for 48 h, then treated with water (20 mL) and acidified with 2 M hydrochloric acid (20 mL). The organic phase was separated and the aqueous phase was extracted with ether (4×30 mL). The combined organic phases were dried with anhydrous magnesium sulfate and concentrated in vacuo yielding brown solid. The residue was purified by column chromatography (silica gel Fluka 60, benzene) yielding 3-(2-methylbenzo[b]furan-5-yl)prop-2-yn-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][C:15]1[C:19](B2OC(C)(C)C(C)(C)O2)=[C:18]([CH3:29])[O:17][N:16]=1.O.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O>[NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:19]2[C:15]([CH3:14])=[N:16][O:17][C:18]=2[CH3:29])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(F)cc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(-c2c(C)noc2C)c(F)cc1N
Temperature: 120 °C

Procedure:
To methyl 2-amino-5-bromo-4-fluorobenzoate (20 g, 80.6 mol.) and 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (24.2 g, 108.9 mol., 1.35 mmol) was added to a solvent mixture of 1,2-dimethoxymethane (120 ml) and water (60 ml). To the above mixture were added PEPPSI-Ipr (3120 mg, 4.2 mmol, 0.05 equiv.) and Cs2CO3 (78.8 g, 241 mol., 3 equiv.). The reaction mixture was heated at 120° C. for 2 h in a pressure tube. The reaction mixture was then diluted with EtOAc (100 ml), washed with bring (50 ml×2). The organic solvent was evaporated and the residue was dissolved in DCM and purified with combi-flash column chromatography (product came out at 50% EtOAc/Hexane) to afford methyl 2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorobenzoate.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1)[CH3:2].[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].O1[CH2:21][CH2:20]CC1>>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:4]1[N:3]([CH2:1][CH3:2])[C:14]2[CH:13]=[CH:12][CH:20]=[CH:21][C:15]=2[N:5]=1)[CH3:2]
Reactant: [Li]CCCC
Reactant: CCn1cnc2ccccc21
Reactant: C1CCOC1
Product: CCn1c(-c2nc3ccccc3n2CC)nc2ccccc21

Procedure:
To a flask were added 2.0 g 1-ethyl-1H-benzimidazole and 25 ml tetrahydrofuran under nitrogen. To this solution was added 20 ml n-butyllitium (1.6M) and the mixture was heated to 60 C for 72 hours. After cooling to 22 C, the reaction was quenched with water and extracted with ethyl acetate. Following solvent removal, the product was dissolved in 8.5 ml hot ethyl acetate and 20 ml of hexane were added. After cooling to 5 C, the product precipitated and was filtered, washed with hexane, and dried giving 0.42 g pale yellow solid.