Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]N(C)C(=O)CCC)=[C:20]([F:33])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:37]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:35]=[CH:34][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])[S:25][CH:3]([CH2:2][CH3:12])[C:4]([NH:6][CH3:7])=[O:5])=[C:20]([F:33])[CH:19]=1
Reactant: CCCC(=O)N(C)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: CCC(SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)C(=O)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.0 g of 2,6-difluorobenzoylisocyanate in 5 ml of a 1:1 v:v mixture of toluene and petroleum ether was added at room temperature over 30 minutes to a stirred solution of 4.4 g of 33 in 20 ml of the same solvent. After stirring at room temperature for 2 hours, the mixture was filtered, and the collected solid product was recrystallized from a mixture of diethyl ether and petroleum ether to give 36, as a white solid, m.p.: 136°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:11])([Cl:10])[Cl:9])=[CH:4][N:3]=1.[Cl:12]Cl>>[Cl:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([C:8]([Cl:9])([Cl:10])[Cl:11])=[CH:4][N:3]=1
Reactant: ClCl
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cn1
Product: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl

Procedure:
In similar operations, various pressure and temperature conditions as described herein are employed when reacting 2-chloro-5-(trichloromethyl)pyridine with an effective amount of Cl2 in the absence of a catalyst resulting in the formation of 2,3-dichloro-5-(trichloromethyl)pyridine. The desired product can be isolated by distillation from the reaction mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:10][N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1.C([O-])([O-])=O.[Na+].[Na+]>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:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([C:14]2[CH:13]=[N:12][N:11]([CH3:10])[CH:15]=2)=[CH:7][N:6]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)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: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc(F)c(F)c2)cn1
Temperature: 80 °C
Yield: 78.5 %

Procedure:
A mixture of 5-bromo-2,3-difluoropyridine (1.9 g, 9.79 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.038 g, 9.79 mmol), Na2CO3 (2.076 g, 19.59 mmol) and Pd(PPh3)4 (1.131 g, 0.979 mmol) in DMF (8 ml) was bubbled with N2 for 10 min and was then heated to 80° C. for 10 h. After being cooled to rt, the mixture was filtered and the filtrate was diluted with EA, washed with water and brine, dried over anhydrous MgSO4. Filtered and concentrated. The residue was purified by silica gel chromatography eluted with Hex/EA (from 100% to 20%) to afford the title compound as a white solid (1.5 g, 57.4% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, 3H), 7.99 (d, 1H), 3.87 (s, 3H). LCMS (method B): [M+H]+=196, tR=1.91 min.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[C:7]([N:15]=[C:16]=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[C:7]([NH:15][C:16]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCC(F)(F)F
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NCC(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
Dissolve trifluoroethylamine (2.2 g, 22 mmol) in chloroform (20 mL) and add the solution to a mixture of benzoyl isothiocyanate (3.5 g, 22 mmol) in chloroform (20 mL) at room temperature. Stir the mixture in a sealed flask for 16 h at room temperature. Concentrate the mixture in vacuo to obtain the desired intermediate as a solid (5.5 g, 95%). MS (ES+) m/z: 263 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[CH:7]=3)=[CH:4][C:3]=1[F:20].N#N.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([NH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[CH:7]=3)=[CH:4][C:3]=1[F:20])(=[O:31])[CH3:30]
Reactant: CCCCC12CCC(=O)C=C1c1cc(F)c(N)cc1C2
Reactant: CC(=O)Cl
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC12CCC(=O)C=C1c1cc(F)c(NC(C)=O)cc1C2
Reaction time: 4.5 h
Yield: 85.1 %

Procedure:
A solution of 7-amino-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.12 g, 4.1 mmol) in anhydrous CH2Cl2 (13.7 mL) was purged with N2, cooled in an ice bath, and treated with pyridine (0.33 mL, 4.1 mmol) followed by acetyl chloride (0.65 mL, 9 mmol). After stirring at 0–5° C. for 4.5 hours, the reaction mixture was partitioned between water and EtOAc. The organic portion was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to provide 7-(acetylamino)-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.1 g) as an orange foam. This material was used without further purification.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2C[CH:10](C)[CH2:11][CH2:12][C:6]=2[C:5]=1[C:14]([O:16]C)=O)=[C:2]=[S:3].[CH3:18][C:19]1[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=1>>[CH3:18][C:19]1[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH2:26][N:27]2[C:14](=[O:16])[C:5]3[C:6]4[CH2:12][CH2:11][CH2:10][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:23]=1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCC(C)C2
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3sc4c(c3c2=O)CCC4)cn1

Procedure:
The compound was synthesized starting from methyl 4,5,6,7-tetrahydro-2-isothiocyanato-6-methylbenzo[b]thiophene-3-carboxylate (0.099 g. 0.37 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.051 g, 0.37 mmol) as described above.
Reaction SMILES: [C:1]([C:5]([OH:7])=[O:6])([F:4])([F:3])[F:2].C([O:12][C:13](=[O:35])[C@H:14]([CH3:34])[NH:15][S:16]([C:19]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:33])=[CH:24][N:25]=[C:26]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:21][CH:20]=1)(=[O:18])=[O:17])(C)(C)C>C(Cl)Cl>[F:2][C:1]([F:4])([F:3])[C:5]([OH:7])=[O:6].[Cl:33][C:23]1[C:22]2[C:27](=[CH:28][C:19]([S:16]([NH:15][C@H:14]([C:13]([OH:35])=[O:12])[CH3:34])(=[O:17])=[O:18])=[CH:20][CH:21]=2)[C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[N:25][CH:24]=1
Reactant: C[C@H](NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
CF3CO2H (1.0 mL) was added to a stirred solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-alanine t-butyl ester (ca. 150 mg, 0.35 mmol) in CH2Cl2 (3.0 mL) and the mixture stirred at room temperature for 2 h. The mixture was evaporated in vacuo, azeotroping with PhMe and CH2Cl2, and then triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-alanine trifluoroacetate (62 mg, 0.126 mmol) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][C:8]([O:10][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (13.20 g, 75.8 mmol) in N,N-dimethylformamide (25 ml) was treated at 22° C. with imidazole (10.56 g, 0.155 mmol) followed by tert-butyldimethylsilyl chloride (12.0 g, 79.6 mmol) and the resulting mixture was stirred at 22° C. for 18 hours. The reaction mixture was then diluted with toluene (500 ml), washed with water (×3), saturated sodium bicarbonate and brine. After drying (magnesium sulfate), the solvent was evaporated under reduced pressure to give an oil. Distillation under vacuum gave 20.9 g (96% yield) of the title material as a clear oil: Bp 80–90° C./0.1 torr (bulb to bulb distillation, air bath temperature). 1H NMR (400 MHz, CDCl3) δ: 0.33 (s, 3), 0.36 (s, 3), 1.00 (s, 9), 1.11 (s, 3), 1.37 (s, 3), 2.72 (m, 2), 4.35 (dd, 1, J=4, 6).
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=1)[C:3]#[C:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1/[C:7](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:8](=[O:14])[NH:9]2.O.[Cl-].[NH4+]>CO.[Zn]>[NH2:29][C:25]1[CH:24]=[C:23]([CH:2]([OH:1])[C:3]#[C:4][C:5]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:6]=2/[C:7](=[CH:15]/[C:16]2[NH:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])/[C:8](=[O:14])[NH:9]3)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccc([N+](=O)[O-])c3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccc(N)c3)c21

Procedure:
rac-(Z)-1,3-Dihydro-4-[3-hydroxy-3-(3-nitrophenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (25 mg, 0.068 mmol) (from Example 60) was added to 10% H2O in methanol (2 mL) and to this mixture was added zinc dust (35 mg, 0.53 mmol) and ammonium chloride (10 mg, 0.19 mmol). The reaction was heated at reflux for 3 h, at which time the reaction was cooled and the solid was filtered off. The solids were washed extensively with ethyl acetate, and the ethyl acetate and methanol were evaporated in vacuo. The resulting precipitate was filtered off, dried and recrystallized from ethyl acetate/hexane to give rac-(Z)-4-[3-(3-aminophenyl)-3-hydroxy-1-propynyl]-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 19 mg, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc(C#N)cn1
Yield: 44.2 %

Procedure:
(S)-2-Aminomethylpyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g), 6-chloronicotinonitrile (0.21 g), potassium carbonate (0.41 g) and diisopropylethylamine (0.78 ml) were heated in xylene at 130° C. for 26 h, cooled and the mixture filtered through kieselguhr. The filtrate was evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate-hexane mixtures to afford the title compound (0.2 g). Mass Spectrum (API+): Found 303 (MH+). C16H22N4O2 requires 302.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:11]([OH:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)=[CH:3][CH:2]=1.[F-].[K+].Br[CH2:20][N:21]1[C:25](=[O:26])[C:24]2[C:27]([CH:33]([CH3:35])[CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[S:22]1(=[O:37])=[O:36]>CN(C=O)C>[CH:33]([C:27]1[C:24]2[C:25](=[O:26])[N:21]([CH2:20][O:12][C:11]3[N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[N:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=3)[S:22](=[O:37])(=[O:36])[C:23]=2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([CH3:35])[CH3:34]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccncc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccncc1)C2=O
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
To a mixture of 1-(4-pyridyl)-3-trifluoromethyl-5-hydroxypyrazole (316 mg; 1.36 mmol) in DMF (20 ml) was added 128 mg (2.24 mmol) of KF at room temperature under nitrogen, and the mixture was stirred for 20 minutes. To the above solution was added 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (400 mg, 1.12 mmol) and the resulting mixture was stirred at room temperature for 45 minutes. The above mixture was quenched with ice/saturated ammonium chloride, extracted with ether (3×) and the organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residual yellow solid was purified by column chromatography (silica gel; 30-50% ethyl acetate in hexane) to afford 240 mg (43%) of 4-isopropyl-6-methoxy-2-[1-(4-pyridyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-pyridyl; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 161°-162° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:27]=[CH:26][C:25]([CH:28]6[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]6)=[CH:24][CH:23]=5)[CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[N:9]2)[CH:2]=1>C(O)(C(F)(F)F)=O.CO>[NH:31]1[CH2:32][CH2:33][CH:28]([C:25]2[CH:26]=[CH:27][C:22]([C:19]3[CH:20]=[C:21]4[C:13]([C:11]5[CH:10]=[N:9][N:8]([CH2:7][C:3]6[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=6)[CH:12]=5)=[CH:14][NH:15][C:16]4=[N:17][CH:18]=3)=[CH:23][CH:24]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccnc6)c5)c4c3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1cncc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)c1
Yield: 15.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (120 mg, 0.224 mmol) was deprotected in TFA/methanol (5/5 ml). This afforded 15 mg (12% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.76 (s, 2H), 8.56-8.55 (d, 2H), 8.36-8.34 (m, 2H), 8.02 (s, 1H), 7.95-7.91 (m, 1H), 7.75-7.72 (m, 3H), 7.45-7.42 (m, 2H), 5.66 (s, 2H), 3.56-3.51 (d, 2H), 3.22-3.14 (t, 2H), 3.10-2.99 (m, 1H), 2.16-2.11 (d, 2H), 2.03-1.93 (td, 2H). MS: m/z=435.2 (M+1), HPLC: 97.0% in method A.
Reaction SMILES: [OH:1][C@H:2]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:29][C:30]1[S:31][CH:32]=[C:33]([CH2:35][C:36](O)=[O:37])[N:34]=1>>[OH:1][C@H:2]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:36](=[O:37])[CH2:35][C:33]2[N:34]=[C:30]([CH3:29])[S:31][CH:32]=2)=[CH:18][CH:19]=1)[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(N)cc1)C[C@H](O)COc1ccccc1
Reactant: Cc1nc(CC(=O)O)cs1
Product: Cc1nc(CC(=O)Nc2ccc(CCN(C[C@H](O)COc3ccccc3)C(=O)OC(C)(C)C)cc2)cs1
Yield: 90.6 %

Procedure:
621 mg of t-butyl (S)-N- (2-hydroxy-3-phenoxypropyl)-N-[2-(4-aminophenyl)ethyl]carbamate and 403 mg of 2-(2-methylthiazol-4-yl)acetic acid were subjected to an amidation reaction to obtain 765 mg of t-butyl (S)-N-(2-hydroxy-3-phenoxypropyl)-N-[2-[4-[[2-(2-methylthiazol-4-yl)acetyl]-amino]phenyl]ethyl]carbamate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][NH:5][C:4](=[O:9])[N:3]=1.C(O[CH:14]1[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:16]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([CH:31]([F:33])[F:32])[O:15]1)(=O)C.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>CC#N>[C:20]([O:19][C@@H:18]1[C@H:17]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:16]([CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH:31]([F:32])[F:33])[O:15][C@H:14]1[N:5]1[CH:6]=[C:7]([Cl:8])[C:2]([NH2:1])=[N:3][C:4]1=[O:9])(=[O:22])[CH3:21]
Reactant: Nc1nc(=O)[nH]cc1Cl
Reactant: CC(=O)OC1O[C@@](COCc2ccccc2)(C(F)F)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](n2cc(Cl)c(N)nc2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
To a solution of 4-amino-5-chloropyrimidin-2(1H)-one 28 (0.336 g, 2.33 mmol) in anhydrous CH3CN (10 mL) was added BSA (0.945 g, 4.64 mmol) portion-wise while maintaining the reaction temperature at 25° C. After the reaction mixture became clear, compound 5 (0.54 g, 1.16 mmol) in CH3CN (2 mL) and SnCl4 (1.2 g, 4.64 mmol) was added into the mixture. The mixture was stirred at 65° C. for 1 h, then cooled and poured into saturated NaHCO3 solution (20 mL). The organic phase was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Purification by flash silica gel chromatography [dichloromethane:methanol (40:1)] gave 29 as a white solid (0.24 g, 31%). LC-MS: (M+H)+=550.1
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:16][CH2:17][CH2:18][Cl:19])[C:6]([O:8]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[C:1]([O:4][CH:5]([CH2:16][CH2:17][CH2:18][Cl:19])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CCCCl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC(CCCCl)C(=O)O
Yield: 94.7 %

Procedure:
Benzyl 2-acetoxy-5-chloropentanoate (52.6 g, 0.19 mol) was dissolved in ethyl acetate (350 ml) and acetic acid (25 ml) and hydrogenated at 10 psi in a Parr apparatus in the presence of a Pd/C catalyst (5%, 2.5 g). After completion, the catalyst was filtered off and the volatiles were evaporated. The residue was dried in vacuo (1 mm Hg, 100° C.), and 35 g (98%) of the crude product was isolated and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[Cl:16][C:12]1[C:11]([F:17])=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1cccc(Cl)c1F
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1c(Cl)cccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(3-chloro-2-fluorobenzyloxy)pyridine (2.00 g, 0.0079 mol), 4chlorophenyl isothiocyanate (1.61 g, 0.0095 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield2.37 g (71%),m.p. 174°-176 ° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH3:36])[C:14]([N:16]([CH2:26][C:27]1[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[S:30][CH:31]=1)[C@@H:17]([CH3:25])[CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[O:15]>>[S:30]1[CH:31]=[C:27]([CH2:26][N:16]([C@@H:17]([CH3:25])[CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[C:14](=[O:15])[C@@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH3:36])[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]1=2
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Product: CCNC(=O)NOCC(=O)N[C@@H](C)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 67 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][O:21][C:22](=[O:42])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]OS(C)(=O)=O>>[CH3:20][O:21][C:22](=[O:42])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCOc2c1ccc(O)c2Cc1ccccc1
Reactant: COC(=O)CCc1ccccc1OCCCCCOS(C)(=O)=O
Product: COC(=O)CCc1ccccc1OCCCCCOc1ccc2c(c1Cc1ccccc1)OCCC2=O
Yield: 91.5 %

Procedure:
Using the procedure of example 11 and starting with 1.2 g (4.72 mmol) of 2,3-dihydro-7-hydroxy-8-(phenylmethyl)-4H-1-benzopyran-4-one (from example 70) and 1.64 g (4.76 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]benzenepropanoic acid methyl ester (from example 72), 2-[5-[(3,4-dihydro-4-oxo-8-(phenylmethyl)-2H-1 -benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester was obtained in 91.5% yield (2.17 g) as a yellow oil. This diester (4.32 mmol) was saponified with 6.5 mL of 3N aqueous lithium hydroxide in 21 mL of tetrahydrofuran, at room temperature, for 48 hr. Work-up as in example 4 gave 2-[5-[(3,4-dihydro-4-oxo-8-(phenylmethyl)-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid as an oil. This material was flash chromatographed on silica gel eluting with ethyl acetate-hexane mixtures giving 1.0 g (47.6%) of pure acid as a solid. Recrystallization from ethyl acetate-ether gave a colorless solid, mp 117°-118° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:6][C:3]=1[C:4]#[N:5].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:34])[CH3:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:8]1[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:34][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH3:33])[N:9]=1
Reactant: Cc1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(Cl)cc2Cl)cc1
Reactant: CC(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C#N)c(OC(C)c3ccc(F)cc3)nc2-c2ccc(Cl)cc2Cl)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To an oven-dried round bottom flask was added toluene (1 mL), the product of Step D of Example 114 (0.050 g; 0.134 mmol); 1-(4-flourophenyl)ethanol (0.070 mL; 0.536 mmol), and cesium carbonate (0.218 g; 0.670 mmol). The reaction mixture was heated at 100° C. and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, then it was partitioned between ethyl acetate and 2N aq. NaOH solution. The organic portion was separated and washed with more 2N aq. NaOH solution (2×), brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-10% ethyl acetate:hexane) to afford 0.051 g of the desired product: m/e=355 (M-1-(4-flourophenyl)ethyl group) Rt=4.9 min on LCMS.