Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]([N:5]([CH2:23][CH:24]1[CH2:28][O:27][C:26](=[O:29])[O:25]1)[C:6]1[C:11](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=[C:8]([O:21][CH3:22])[N:7]=1)=[O:4].[H][H]>C(O)C.[Pd]>[CH3:30][C:2]([CH3:1])([CH3:31])[C:3]([N:5]([CH2:23][CH:24]1[CH2:28][O:27][C:26](=[O:29])[O:25]1)[C:6]1[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:10][CH:9]=[C:8]([O:21][CH3:22])[N:7]=1)=[O:4]
Reactant: CCCCOC(=O)/C=C/c1ccc(OC)nc1N(CC1COC(=O)O1)C(=O)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(=O)CCc1ccc(OC)nc1N(CC1COC(=O)O1)C(=O)C(C)(C)C
Yield: 98 %

Procedure:
A solution of butyl (2E)-3-[2-{(2,2-dimethylpropanoyl)[(2-oxo-1,3-dioxolan-4-yl)methyl]amino}-6-(methyloxy)-3-pyridinyl]-2-propenoate (6.156 g, 14.184 mmol) in ethanol (200 ml) was treated with palladium on carbon (10% paste, 1.23 g) and the mixture was then stirred at rt under 1 atmosphere of hydrogen for 18 h. The reaction mixture was then filtered through a thin pad of Celite, eluting with more ethanol (200 ml). The organic filtrate was then evaporated to give the product as a yellow oil (6.065 g, 98%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([N:9]([CH2:18][C:19]2[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Na+].C(O)C.Cl>O>[CH:1]([C:4]1[N:5]=[C:6]([N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:30]=3)=[CH:37][CH:38]=2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(C(C)C)cs3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1csc(N(CCc2ccccc2)Cc2ccc(COc3ccc(CCC(=O)O)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A mixture of methyl 3-{4-[(4-{[(4-isopropyl-1,3-thiazol-2-yl)(2-phenylethyl)amino]methyl}benzyl)oxy]phenyl}propanoate (350 mg), 2N aqueous sodium hydroxide solution (2 mL) and ethanol (5 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (210 mg, yield 62%) as colorless crystals.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH3:21][O:22][C:23](=[O:33])[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C[O:35][C:36](=O)[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCCC1>[CH3:21][O:22][C:23](=[O:33])/[C:24](/[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:36](\[OH:35])/[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]
Reactant: COC(=O)COCc1ccccc1
Reactant: COC(=O)C(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
Lithium diisopropylamide was generated by addition of n-butyl lithium (17 mL, 1.9M in hexane, 33.33 mmol), di-isopropyl amine (4.66 mL, 33.33 mmol) in tetrahydrofuran (15 mL) at 0° C. and stirred for 10 min. In a separate flask, a mixture of benzyloxy-acetic acid methyl ester (3) (4 g, 22.22 mmol) and oxalic acid tert-butyl ester methyl ester (2) (5.33 g, 33.33 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. and then lithium diisopropylamide was added at −78° C. The mixture was stirred at −78° C. for 1 h. After 1 h, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for another 1 h. After completion of the reaction, the reaction was quenched with 1N HCl, and extracted with ethyl acetate. The separated organic part was dried over sodium sulfate and concentrated under reduced pressure, passed over a normal silica column using 25% ethyl acetate in hexane to get (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (2.4 g, 35%) as ketoenol tautomers and ketone hydrate as a thick light yellow coloured oil. These were immediately used for next step.
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH3:14]>>[NH2:14][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc2nc(S)sc2c1
Product: Nc1nc2ccc([N+](=O)[O-])cc2s1

Procedure:
It has also been reported [see J. Amer. Chem. Soc. 49, 1748 (1927)] that treatment of 2-mercapto-6-nitrobenzothiazole with concentrated aqueous ammonia under pressure at 160° C. followed by crystallization from alcohol and treatment with bone black gives 2-amino-6-nitrobenzothiazole in small yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[CH3:19]I.[H-].[Na+]>CS(C)=O.CCCCC>[Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]2[N:6]([CH3:19])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: CI
Reactant: O=[N+]([O-])c1cc(Br)cc2c1[nH]c1ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CS(C)=O
Product: Cn1c2ccc(Br)cc2c2cc(Br)cc([N+](=O)[O-])c21
Reaction time: 0.03 h

Procedure:
3,6-dibromo-1-nitrocarbazole (3.56 g, 0.01 mole) was dissolved in 30 ml of warm DMSO followed by the addition of 30 ml of CH3I. Then 2.0 g of 50% NaH dispersion in mineral oil (0.02 mole) was washed under N2 with 2×50 ml of pentane, dried under N2 and added rapidly to the DMSO solution. The solution turned purple immediately with H2 evolution and became yellow in two minutes. Addition of 0.25 g of NaH did not cause the yellow slurrY to turn purple indicating that the reaction was complete. Methanol (200 ml) was added cautiously to precipitate the product. The product was recovered by filtration, washed with 25 ml of methanol, 10×25 ml of water, 25 ml of methanol and air dried to give 3.40 g of product, m.p. 225°-226° C. (corrected). [H. Lindemann & F. Muhlhaus, Ber., 58, 2371 (1925) report a m.p. of 221° C. for the product].
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@@:28]4(OC)[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F>C(#N)C.ClC(Cl)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:28]4[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@]1(c2ccc(C(C)C)c(Cc3ccc4c(c3)N(Cc3ccccc3)CCC4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC(Cl)Cl
Solvent: CC#N
Product: CC(C)c1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: -55 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of (2S,3R,4S,5S,6R)-2-[3-(1-benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (1.20 g, 2.19 mmol) in acetonitrile-dichloroethane 1:1 (20 mL) was added triethylsilane (1.39 mL, 8.76 mmol) at room temperature, then the reaction mixture cooled to −50 to −60° C. and boron trifluoride diethyletharate complex (0.55 mL, 4.38 mmol) was added dropwise, and the reaction mixture was stirred at same temperature and allowed to stir at below −30° C. for 2 hours and at −20° C. for 1 hour and then below 0° C. for 1 hour. The reaction was quenched with aq. saturated NaHCO3 solution (20 mL). The volatiles were evaporated under reduced pressure, and the resulting mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined and washed with brine (5 mL), dried over sodium sulphate, and concentrated to furnish (2S,3R,4R,5S,6R)-2-[3-(1-Benzyl-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (1.0 g). Crude product was used for next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([NH2:36])[S:34][CH:35]=2)[N:3]=1
Reactant: Nc1nc(CCl)cs1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(N)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 68.3 mg (0.46 mmol) of 4-chloromethyl-2-amino-1,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 115.9 mg (86.2% of theory) of product.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:13]([O:16][CH:17](O)[C:18](O)=O)(=[O:15])[CH3:14]>C(Cl)(Cl)Cl>[C:13]([O:16][CH2:17][C:18]1[N:4]2[CH:5]=[CH:6][C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:15])[CH3:14]
Reactant: NNc1nccc2ccccc12
Reactant: CC(=O)OC(O)C(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1nnc2c3ccccc3ccn12

Procedure:
1-Hydrazinoisoquinoline was heated with excess acetoxyglycolic acid. The residue was cooled, dissolved in chloroform and washed with sodium carbonate solution. The chloroform extracts were dried and concentrated invacuo to provide the crude product which was purified by recrystallization from benzene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([Cl:25])=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:9]2=[O:24])[CH:7]=1.[C:27](Cl)(Cl)=[O:28]>C1(C)C=CC=CC=1>[Cl:25][C:5]1[CH:4]=[C:3]([F:26])[C:2]([N:1]=[C:27]=[O:28])=[CH:7][C:6]=1[N:8]1[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:9]1=[O:24]
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(N=C=O)c(F)cc2Cl)c1=O

Procedure:
A mixture of isopropyl 3-(5-amino-2-chloro-4-fluorophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (4.0 g, 0.0103 mol) in toluene is treated with a 1.93M solution of phosgene in toluene (19 mL), refluxed for 3 hours, cooled, partially concentrated in vacuo, diluted with toluene, partially concentrated in vacuo, diluted with toluene and concentrated in vacuo to give the title product as a yellow foam which is identified by 1H NMR spectral analysis.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])([CH3:3])[CH3:2].[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].C1CCN2C(=NCCC2)CC1>O>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:16][CH2:15][C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])#[N:10]
Reactant: CC(C)NCc1cccc(C#N)c1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)N(CCC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Temperature: 80 °C

Procedure:
A mixture of 3-[(isopropylamino)methyl]benzonitrile (5.7 g, 32.7 mmol), tert-butyl acrylate (4.78 ml, 32.7 mmol) and DBU (5.0 ml, 32.7 mmol) was heated neat at 80° C. for 24 hours. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. After purification by chromatography (silica, pet ether/EtOAc), the title compound was obtained as a colorless oil. 1H NMR (DMSO-d6, 400 MHz) δ 7.73 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 3.56 (s, 2H), 2.75 (m, 1H), 2.62 (t, J=6.5 Hz, 2H), 2.25 (t, J=6.4 Hz, 2H), 1.39 (s, 9H), 0.83 (d, J=8.8 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[S-:11][C:12]#[N:13].[K+].C(O)C>O>[S:11]([CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[C:12]#[N:13]
Reactant: CC(=O)c1ccccc1Br
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
In accordance with the known process (Beilstein, 8, 94), 10.0 g (50 mmol) of o-bromoacetophenone and 4.9 g (50 mmol) of potassium thiocyanate were added to 80 ml of ethyl alcohol, and the resultant mixture was heated at 80° C. for 3 hours and then allowed to stand overnight. Added to the reaction mixture were 50 ml of water. Precipitated crystals were collected by filtration, washed with 50% aqueous ethyl alcohol and then dried, whereby the title compound was obtained as colorless crystals.
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].P.[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:6]([O:14][P:1]([Cl:4])[Cl:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCO
Reactant: ClP(Cl)Cl
Agent: P
Product: CCCCCCCCOP(Cl)Cl
Temperature: 0 °C

Procedure:
Freshly distilled phosphorus trichloride (45.6 g, 0.338 mole) was charged into a four-necked round bottom flask equipped with a mechanical stirrer, an addition funnel, a thermometer, and a reflux condenser itself topped with a discharge tube. The discharge tube led to an aqueous sodium hydroxide trap for absorption of hydrogen chloride that evolves from the reaction. After cooling the reaction vessel to 0° C. with continual purging of dry nitrogen, anhydrous octanol (22 g, 0.168 mole) was added dropwise to the reaction mixture. When the addition of the octanol was complete, the reaction mixture was allowed to warm gradually up to room temperature and was then poured into a dry distillation flask. The material was distilled with a bath temperature of 80–85° C. and using a water pump vacuum to remove residual hydrogen chloride and excess phosphorus trichloride. The residue was then fractionated at 8 mm Hg to yield the product at 113–130° C. in 69% conversion. The phosphorus-31 NMR showed a peak at 176 ppm. The refractive index at 21.5° C. was 1.4682.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)c(F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
A 500 mL flask was charged with 4-bromo-3-fluorobenzoic acid (5.00 g, 22.83 mmol), 100 mL DMF, morpholine (2.4 ml, 27.5 mmol), and 4-Ethylmorpholine (8.6 ml, 67.9 mmol). HOBt (4.32 g, 32.0 mmol) was added followed by EDC (5.25 g, 27.4 mmol) and the reaction allowed to stir at room temperature for 18 hours. The reaction was concentrated and the resulting orange syrup taken up in 100 mL EtOAc and 100 mL water. The organic layer was washed with 100 mL 2N HCl, 100 mL saturated sodium bicarbonate, and 100 mL saturated sodium chloride. The organic was then dried with MgSO4, filtered, and concentrated to give 6.476 g (98%) of a viscous yellow oil. This material was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCCN(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
1.52 g (10 mmol) of methyl 4-hydroxybenzoate was dissolved in 40 ml of N,N-dimethylformamide and 2.16 g (15 mmol) of 2-dimethylaminoethyl chloride hydrochloride and 4.15 g (30 mmol) of potassium carbonate were further added. The mixture was heated at 80° C. and stirred overnight. After cooling, water was added to the reaction mixture, the obtained mixture was extracted twice with ethyl acetate, and the extract was washed with brine. The organic phase was dried (Na2SO4) and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=70:1 to 15:1 (v/v)) to obtain 0.69 g (3.09 mmol) of methyl 4-(2-dimethylaminoethoxy)benzoate as a pale brown oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [CH:1]1[C:6]2=[CH:7][C:8]3[C:17]([CH:18]=[C:5]2[CH:4]=[CH:3][CH:2]=1)=[CH:16][C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:9]=3.C1(=O)[O:23][CH:22]=[CH:21][O:20]1>>[CH:14]1[C:15]2[CH:16]3[CH:21]([OH:20])[CH:22]([OH:23])[CH:9]([C:10]=2[CH:11]=[CH:12][CH:13]=1)[C:8]1[C:17]3=[CH:18][C:5]2[C:6]([CH:7]=1)=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: O=c1occo1
Reactant: c1ccc2cc3cc4ccccc4cc3cc2c1
Product: OC1C2c3ccccc3C(c3cc4ccccc4cc32)C1O

Procedure:
A mixture of 7.0 g. of benz[b]anthracene and 26 g. of vinylene carbonate is heated at reflux under nitrogen for 20 hours. The excess vinylene carbonate is removed by vacuum distillation (57° C./9 mm.) and the residue is taken up in 25 ml. of methylene chloride and filtered. The filtrate is treated with twice its volume of methanol and then cooled, producing a tan solid and a mother liquor which is saved. This solid is recrystallized from 60 ml. of 1,2-dichloromethane, collected by filtration, washed with methanol and saved. The mother liquor (saved above) is concentrated giving a gummy solid which is recrystallized from a mixture of methylene chloride and methanol giving a gray solid which is combined with the above solid and recrystallized from ethyl acetate with charcoal treatment giving 5,12-dihydro-5,12-ethanobenz[b]anthracene-13,14-diol, cyclic carbonate as colorless rods. A mixture of 1.3 g. of the cyclic carbonate, 1.05 g. of potassium hydroxide, one ml. of water and 15 ml. of ethanol is stirred at 60°-65° C. for 2 hours. The mixture is diluted with 1-2 volumes of water, filtered and the solid is washed with water and dried giving cis-5,12-dihydro-5,12-ethanobenz[b]anthracene-13,14-diol as a colorless solid. To a solution of 2.6 g. of cis-5,12-dihydro-5,12-ethanobenz[b]anthracene-13,14-diol in 400 ml. of glacial acetic acid at 20° C. is added portionwise 4.4 g. of lead tetraacetate. The reaction is stirred for 45 minutes. The weakly purple colored solid is filtered off, washed with glacial acetic acid and finally water and dried leaving 1.0 g. (m.p. 170°-172° C.) of 5,12-dihydro-5,12-benz[b]anthracene dicarboxaldehyde.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[CH:8]([NH2:13])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:5])([CH3:4])[CH3:3].[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=O.C(N(CC)CC)C>ClCCl>[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=[N:13][CH:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7]([O:6][C:2]([CH3:3])([CH3:5])[CH3:4])=[O:14]
Reactant: O=Cc1nccs1
Reactant: CC(C)CC(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(N=Cc1nccs1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A stirred mixture of 2-amino-4-methyl-pentanoic acid tert-butyl ester, hydrochloride salt (5.00 g, 22.34 mmol), 1,3-thiazole-2-carboxaldehyde (2.53 g, 22.34 mmol) and triethylamine (3.10 mL, 22.3 mmol) in dichloromethane (60 mL) was heated under reflux under nitrogen for 19 hours. The reaction mixture was allowed to cool to room temperature, washed twice with water, dried over Na2SO4 and evaporated to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[CH:9]=[N:8]1)([CH3:6])[C:3](O)=[O:4].C1N=C[N:23](C(N2C=NC=C2)=O)C=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[CH:9]=[N:8]1)([CH3:6])[C:3]([NH2:23])=[O:4]
Reactant: CC(C)(C(=O)O)n1cc(-c2ccnc3[nH]ccc23)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)n1cc(-c2ccnc3[nH]ccc23)cn1
Reaction time: 3 h
Yield: 26.2 %

Procedure:
A mixture of 2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoic acid (23 mg, 0.000085 mol) and N,N-carbonyldiimidazole (CDI) (21 mg, 0.00013 mol) in 2 mL of DMF was stirred for 3 hours. An excess of solid NH4Cl and TEA was added to the mixture and this was stirred for 3 hours. The majority of solvent was removed in vacuo, and the crude residue was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) followed by re-purification via preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford 2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanamide (6 mg, 26%). 1H NMR (400 MHz, d6-DMSO): 11.63 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 7.47 (t, 1H), 7.29 (d, 1H), 7.21 (s, 1H), 6.93 (s, 1H), 6.80 (dd, 1H), 1.77 (s, 6H); MS(ES): 270 (M+1).
Reaction SMILES: C[C@@H](CCC)CCCO[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=O)=[CH:9][CH:8]=1.[CH3:19][C@@H:20]([CH2:35][CH2:36][CH3:37])[CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1>>[CH2:11]([C:10]1[CH:9]=[CH:8][C:7]([O:31][C:30](=[O:32])[C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]([CH3:19])[CH2:35][CH2:36][CH3:37])=[CH:34][CH:33]=2)=[CH:15][CH:14]=1)[CH2:14][CH2:15][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCC[C@H](C)CCCCOc1ccc(C(=O)O)cc1
Reactant: CCC[C@H](C)CCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCc1ccc(OC(=O)c2ccc(OCCCC[C@@H](C)CCC)cc2)cc1

Procedure:
The procedure of Example 8 was followed except that the (S)-4-(4'-methylheptyloxy)benzoic acid was replaced by (S)-4-(5'-methyloctoxy)benzoic acid to thereby give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26]C)=[O:25])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([OH:26])=[O:25])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2cccc(C(=O)OC)c2)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2cccc(C(=O)O)c2)nc1Cl
Yield: 71.3 %

Procedure:
The same operation as in Example (91d) was performed using methyl 3-[(7-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (100c) (0.16 g, 0.35 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and tetrahydrofuran (8 mL), to obtain 0.11 g of the title compound as a light pink solid (71%).