Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([CH2:24][CH3:25])[CH2:22][CH2:21][C@H:17]1[C:18](O)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:28](CC)CC)C.ClC(OCC)=O.N>C1COCC1.O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([CH2:24][CH3:25])[CH2:22][CH2:21][C@H:17]1[C:18]([NH2:28])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC[C@H]1CC[C@@H](C(N)=O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
N-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-proline was mixed with triethylamine (0.426 mL, 3.25 mmol) in THF (4 mL) and cooled to 0° C. followed by the addition of ethyl chloroformate (0.287 mL, 3.0 mmol). After 20 minutes, 0.5 M ammonia in dioxane (6 mL) was added. After 4 hours, the mixture was concentrated, and the residue was partitioned between 1 N HCl and ethyl acetate. The organic extracts were washed with saturated NaHCO3, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash chromatography (80% to 100% ethyl acetate/hexane) to provide the titled compound. MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3(O)[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[O:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:44])CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3([F:44])[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[O:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(NC(=O)C3CN(C(=O)OCc4ccccc4)C3)cc2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccc(NC(=O)C3CN(C(=O)OCc4ccccc4)C3)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(4-(1-((benzyloxy)carbonyl)azetidine-3-carboxamido)phenyl)-4-hydroxypiperidine-1-carboxylate (2.5 g, 4.91 mmol) in 50 mL dichloromethane was cooled to −78° C. and diethylaminosulfur trifluoride was added dropwise via a syringe. The reaction solution was stirred at −78° C. for an additional 1 hour and then warmed to 0° C. The reaction was allowed to stir at 0° C. for 1 hour and was cooled back down to −78° C. The reaction mixture was diluted with 50 mL of dichloromethane followed by quenching with 10 mL methanol. The solution was washed with saturated sodium bicarbonate and brine, dried with magnesium sulfate and filtered. Concentration and normal phase chromatography provided the title compound.
Reaction SMILES: [CH2:1]([C@:8]1([C:23]([NH:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][OH:28])=[O:24])[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([C@:8]1([C:23]([NH:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[O:28])=[O:24])[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)O[C@](Cc2ccccc2)(C(=O)NC(CO)c2ccccc2)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C(=O)O[C@](Cc2ccccc2)(C(=O)NC(C=O)c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To the product from Step A (250 mg, 0.545 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (358 mg, 0.818 mmol) and the mixture was stirred for 30 min. A 1:1 mixture of saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate (20 mL) was added and the mixture was stirred rapidly for 15 min. The layers were separated and the aqueous phase extracted with dichloromethane (3×10 mL). The combined organic phases were washed with saturated aqueous brine (1×15 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo, to afford the crude colorless title compound as an amorphous solid. LC/MS 457.1 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:12]=2[C:13]#[N:14])[CH:7]=[N:8][CH:9]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:22]3[CH:23]=[C:24]4[N:31]([CH3:32])[CH2:30][CH2:29][N:25]4[C:26](=[O:28])[N:27]=3)=[CH:15][C:12]=2[C:13]#[N:14])[CH:7]=[N:8][CH:9]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3cncc(F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (9.83 mg, 0.246 mmol), 2-((5-fluoropyridin-3-yl)oxy)-5-(hydroxymethyl)benzonitrile in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (45.6 mg, 0.246 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:19]([NH:27][C:28]1[CH:40]=[C:39](Br)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C(=O)C>[C:19]([NH:27][C:28]1[CH:40]=[C:39]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccccc3)c2)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
46 mg of 4-(dimethylamino)phenylboronic acid, 49 mg of sodium carbonate and 5.7 mg of polymer supported di(acetato)dicyclohexylphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature 5.7 mg polymer supported di(acetato)dicyclohexylphenylphosphine palladium(II) was added and stirred at 110° C. for 24 hours, After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(benzamido)-4-(4-(dimethylamino)phenyl)benzoate.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]([C:15]2[CH:20]=[CH:19]C(C3OCC(C)(C)N=3)=[CH:17][CH:16]=2)=[CH2:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.ClCCl.[C:34]([O:37]CC)(=[O:36])[CH3:35]>C(O)C>[C:1]([N:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]([C:15]2[CH:16]=[CH:17][C:35]([C:34]([OH:37])=[O:36])=[CH:19][CH:20]=2)=[CH2:14])=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(c1ccc(C2=NC(C)(C)CO2)cc1)c1cc(C(C)C)n(C(C)(C)C)n1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: C=C(c1ccc(C(=O)O)cc1)c1cc(C(C)C)n(C(C)(C)C)n1
Temperature: 100 °C

Procedure:
To 5 ml of 130 mg of a-(1-tert-butyl-5-isopropylpyrazol-3-yl)-4-(4,4-dimethyl-1,3-oxazolin-2-yl)styrene in ethanol was added 0.4 ml of a 3N aqueous solution of an acid at room temperature. The resulting mixture was heated under reflux for 30 minutes. To the reaction mixture was added a 5N aqueous solution of sodium hydroxide to adjust its pH to 11, followed by extraction with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced -pressure. To a solution of the residue in 3 ml of 1,4-dioxane were added 100 mg of lithium hydroxide and the resulting mixture was heated at 100° C. for 2 hours. After the completion of the reaction, a 3N aqueous solution of hydrochloric acid was added to adjust the pH to 5, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 50% dichloromethane/ethyl acetate), whereby 4 mg of the title compound were obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([N:42]2[C:46](=[O:47])[CH:45]=[CH:44][C:43]2=[O:48])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[O:48]=[C:43]1[CH:44]=[CH:45][C:46](=[O:47])[N:42]1[C:39]1[CH:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1
Reactant: O=C=Nc1ccc(N2C(=O)C=CC2=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2C(=O)C=CC2=O)cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (32.4 mg, 0.32 mmol) (Aldrich), followed by the addition of 1-(4-isocyanato-phenyl)-pyrrole-2,5-dione (50 mg, 0.23 mmol) (Fluka). The mixture was stirred at room temperature for 0.5 hour. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid [4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-phenyl)-amide as a white solid (Yield 35 mg, 28%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)C(C)C)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)=[O:27])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: N#Cc1cc(Br)ccc1N
Reactant: O=C(Cl)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: N#Cc1cc(Br)ccc1NC(=O)c1ccccn1
Yield: 70.9 %

Procedure:
To a stirred solution of 2-amino-5-bromobenzonitrile 2-1 (2.8 g, 0.014 moles) in toluene was added (4.95 mL, 0.028 moles) of N,N-diisopropylethylamine, followed by slow addition of (2.74 g, 0.015 moles) picolinoyl chloride. The mixture was stirred until complete by TLC. Reaction was filtered and dried under vacuum to afford 3 grams of 2-2. Analytical LCMS: (CH3CN/H2O/1% TFA, 4 min gradient), 95% pure, M+1 peak m/e 301.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[NH2:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22]>>[C:21]([C:23]1[CH:28]=[C:27]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:22])[NH2:20]
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: NC(=O)c1cccc(B(O)O)c1
Product: NC(=O)c1cccc(-c2ccc(OCc3nc(C(=O)O)cs3)cc2)c1

Procedure:
2-(3′-Carbamoyl-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure 2 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and (3-aminocarbonylphenyl)boronic acid (available from Apollo Scientific Ltd., Stockport, UK). Mass spectrum MH+=355.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:9]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(N2CC[C@@H](O)C2)c(F)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
3-Fluoro-4-((3R)-3-hydroxy-1-pyrrolidinyl)nitrobenzene (35.8 g, 0.158 M) was dissolved in DMF (200 ml), and treated with imidazole (21.6 g, 0.318 M) and t-butyldimethylsilyl chloride (35.7 g, 0.239 M) and stirred for 18 hours at ambient temperature under nitrogen. Solvent was evaporated, and the residue treated with EtOAc (300 ml) and water (200 ml). The organic layer was washed with water (150 ml) and dried (magnesium sulfate). Evaporation gave the desired product (54 g), of sufficient quality for use without purification.
Reaction SMILES: C(OC1C=NC(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)=NC=1)C.Cl.[CH:36]1([C:39]2[C:40]([NH:49][C@H:50]3[CH2:54][CH2:53][CH2:52][C@@H:51]3[NH2:55])=[N:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH2:38][CH2:37]1.[N:56]1[N:57]([C:61]2[C:62]([C:67](O)=[O:68])=[N:63][CH:64]=[CH:65][CH:66]=2)[N:58]=[CH:59][CH:60]=1>>[CH:36]1([C:39]2[C:40]([NH:49][C@H:50]3[CH2:54][CH2:53][CH2:52][C@@H:51]3[NH:55][C:67]([C:62]3[C:61]([N:57]4[N:58]=[CH:59][CH:60]=[N:56]4)=[CH:66][CH:65]=[CH:64][N:63]=3)=[O:68])=[N:41][CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[N:44]=2)[CH2:37][CH2:38]1
Reactant: O=C(O)c1ncccc1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1
Agent: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(5-Ethoxypyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 135) from (1S,2S)-1-N-[3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 48; 105 mg, 0.33 mmol) and 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 74 mg, 0.39 mmol) except after work-up, the organics were loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM, then methanol and 2M ammonia in methanol and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:17](Cl)(=O)C>CO>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[CH2:3][C:4]([O:6][CH3:17])=[O:5]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To a stirred suspension of 3-amino-3-(3',4'-dimethoxyphenyl)propionic acid (70.1 grams, 312 mmol) in methanol (400 mL) at 0° C., was added acetyl chloride (47.6 mL, 667 mmol) dropwise. After an additional 15 minutes, the ice-water bath was removed. The resulting clear solution was stirred at room temperature for 2 hours. The system was opened and the solvent was blown off with N2 overnight. To the solid was added methanol (50 mL) and ether (300 mL). The resulting suspension was stirred at room temperature for 1 hour. The suspension was filtered and the solid was washed with ether (100 mL). The solid was dissolved in a mixture of sodium carbonate (200 mL, sat), water (200 mL), and methylene chloride (250 mL). The organic layer was separated. The aqueous layer was extracted with methylene chloride (3×250 mL). The combined organic layers were dried over magnesium sulfate. Removal of solvent gave methyl 3-amino-3-(3',4'-dimethoxyphenyl)propionate as an oil (60.2 grams, 81% yield): 1H NMR (CDCl3)δ1.77 (s, 2H, NH2), 2.65 (d, J=7 Hz, 2H, CH2), 3.68 (s, 3H, CH3), 3.87 (s, 3H, CH3), 3.89 (s, 3H, CH3), 4.39 (t, J=Hz, 1H, CH), 6.81-6.93 (m, 3H, Ar); 13C NMR (CDCl3)δ44.00, 51.48, 52.18, 55.72, 55.76, 109.20, 111.02, 118.02, 137.21, 148.11, 148.93, 172.34; Anal. Calcd for C12H17NO4 0.1 H2OC, 59.19; H, 7.19; N, 5.81. Found: C, 59.38; H, 7.09; N, 5.91.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[CH2:16])[C:12]([O:14]C)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[CH2:16])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C(=O)OC)c1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C(=O)O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
Accordingly, as shown in step iii of Scheme 1, methyl 2-(quinolin-6-yl)acrylate (75.0 g) was dissolved in a solution containing sodium hydroxide (65.2 g, 1.63 mol) in 1.1 liters of tetrahydrofuran and 1.1 liters of water. The reaction was stirred at room temperature overnight. The organic layer was partitioned off and the aqueous layer washed with 500 mL of toluene. The aqueous layer was then cooled with an ice bath and acidified by dropwise addition of concentrated HCl until a pH of 4.5 was achieved (about 125 mL of conc. HCl, 1.508 mol), resulting in a white precipitate. After the addition was complete, the reaction was stirred for an additional 0.5 hour at 5° C. The precipitate was collected by vacuum filtration, washed with water, washed with methyl t-butyl ether, and dried under vacuum to afford 2-(quinolin-6-yl)acrylic acid (compound 1003, 36.2 g): ESMS (M+1), 200.06; 1H NMR (300.0 MHz, DMSO-d6) δ 13.01 (1H, s), 8.91 (1H, dd, J=1.8, 4.2 Hz), 8.40 (1H, d, J=7.5 Hz), 8.07 (1H, d, J=1.8 Hz), 8.01 (1H, d, J=8.7 Hz), 7.84 (1H, dd, J=1.9, 8.9 Hz), 7.55 (1H, dd, J=1.2, 8.4 Hz), 6.39 (1H, d, J=0.9 Hz), 6.17 (1H, d, J=0.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])[CH3:8].[N:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[C:18]=[O:19]>C1COCC1.CN(C1C=CN=CC=1)C>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[NH:17][C:18](=[O:19])[O:11][CH2:10][CH2:9][N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[Cl:1])=[O:12]
Reactant: CN(CCO)C(=O)NCc1ccccc1Cl
Reactant: O=C=Nc1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CN(CCOC(=O)Nc1ccc2ccccc2c1)C(=O)NCc1ccccc1Cl
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a solution of 3-(2-chlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (120 mg, 0.50 mmol) in THF (1.0 mL) were added DMAP (3.0 mg, 0.02) and 2-isocyanatonaphthalene (100 mg, 0.60 mmol). The reaction mixture was stirred for 30 min. LC/MS indicated the completion of the reaction. The mixture was filtered and the filtrate was purified by RP-HPLC using a mixture of acetonitrile and H2O to give 2-(3-(2-chlorobenzyl)-1-methylureido)ethyl naphthalen-2-ylcarbamate (165 mg, 80%). LRMS (M-Boc+H+) m/z 412.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@@H:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:18])[N:10]([CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:11]([CH3:17])[C:12]([N:14]([CH3:15])[CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](C(=O)N(C)C)N(CCOCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Under nitrogen atmosphere, to a solution of 2.78 g of the compound obtained in Step 79-1 in DMF (30 ml) was added 0.66 g of NaH under ice cooling. The solution was stirred at room temperature for one hour, then, 3.58 g of [(2-bromoethoxy)methyl]benzene was added. The solution was stirred at room temperature for two hours, then, water was added, and the resulting mixture was extracted with EtOAc. The organic layers were combined, washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: n-hexane/EtOAc=2/3; v/v) to obtain 3.22 g of the title compound (pale yellow oil).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][C:17]3=[O:18])=[CH:12][CH:11]=2)=[O:9])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:31](Br)[CH3:32]>CN(C)C=O>[CH2:31]([N:7]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][C:17]2=[O:18])=[CH:12][CH:11]=1)=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=1)[CH3:32]
Reactant: CCBr
Reactant: COc1ccc(NC(=O)c2ccc(N3C(=O)CCc4ccccc43)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccc(N2C(=O)CCc3ccccc32)cc1)c1ccc(OC)cc1
Yield: 55.8 %

Procedure:
To a solution of 1-[4-(4-methoxyanilinocarbonyl)phenyl]-3,4-dihydrocarbostyril (0.2 g) in dimethylformamide (15 ml) is added 60 % sodium hydride (24 mg) with stirring under ice cooling and the mixture is stirred at room temperature for 0.5 hour. Then, thereto is added a solution of ethyl bromide (64 mg) in dimethylformamide (DMF, 1 ml) and the mixture is refluxed with heating for 1 hour. DMF is distilled off under reduced pressure and water is added to the residue and the mixture is extracted with dichloromethane. The extract is washed with water and dried with magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography to give 1-[4-(N-ethyl-4-methoxyanilinocarbonyl)phenyl]-3,4-dihydrocarbostyril (0.12 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([CH3:11])=[N:7][C:6]=2[C:5]([Cl:12])=[CH:4][C:3]=1[F:13].[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:12][C:5]1[C:6]2[N:7]=[C:8]([CH3:11])[S:9][C:10]=2[C:2]([N:1]=[C:15]=[O:14])=[C:3]([F:13])[CH:4]=1
Reactant: Cc1nc2c(Cl)cc(F)c(N)c2s1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc2c(Cl)cc(F)c(N=C=O)c2s1

Procedure:
A solution of 3.2 g (15 mmol) of 7-amino-4-chloro-6-fluoro-2-methylbenzothiazole and 15 g (76 mmol) of diphosgene in 150 ml of toluene was refluxed for 6 hours. The crude product obtained after evaporation was converted directly into active ingredient I.15.