Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-])=[O:6])[CH:3]=1.[CH3:14][NH:15][CH3:16].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>C1COCC1.CO.O>[CH3:14][N:15]([CH3:16])[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Methyl isophthalate (2.00 g, 11.1 mmol) was dissolved in THF (60 mL), and a 2.0 mol/L solution of dimethylamine (11.1 ml, 22.2 mmol) in methanol, EDC hydrochloride (4.27 g, 22.2 mmol) and 1-hydroxybenzotriazole monohydrate (3.40 g, 22.2 mmol) were added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:3) to afford methyl 3-(N,N-dimethylcarbamoyl)benzoate (2.30 g, 100%).
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.Cl>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[O:21])[CH2:14][S:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:20]
Reactant: CCOC(=O)C(=O)CBr
Reactant: O=c1[nH]c(S)nc2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CSc1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 36 h
Yield: 11 %

Procedure:
An homogeneous solution of 2-mercapto-3H-quinazolin-4-one (1.30 g, 7.17 mmol) and ethyl bromopyruvate (1 mL, 7.17 mmol, 90% purity) in DMF (30 mL) was stirred at room temperature for 6 h. Triethylamine (5 mL) was added to the solution and the mixture was stirred at room temperature for 36 h. The mixture was acidified to pH 1-2 with concentrated hydrochloric acid and then rotary evaporated to dryness. The residue was separated by column chromatography eluted with EtOAc giving the title compound as yellow solid (0.231 g, yield 11.0%). 1H NMR (DMSO-d6, 300.16 MHz) δ (ppm): 8.05 (dd, J=7.9 & 1.4 Hz, 1H), 8.01 (s, 1H), 7.81 (td, J=8.3 & 1.5 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.46 (td, J=7.5 & 1.4 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.82 (d, J=12.2 Hz, 1H), 3.46 (d, J=12.2 Hz, 1H) and 1.18 (t, J=7.1 Hz, 3H). 13C NMR (DMSO-d6, 75.48 MHz) δ (ppm): 168.06, 159.54, 159.26, 149.07, 135.98, 126.85, 126.74, 126.36, 119.09, 91.33, 62.79, 37.92 and 14.31. MS (ESI) m/z: 293 (M++H, 100).
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>C(O)C>[C:19]1(=[O:28])[N:18]([CH2:17][CH2:16][S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: Sc1ccccn1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCSc1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
Triethylamine [12.54 ml (90 mmol)] was added to a suspension of 6.67 g (60 mmol) of 2-mercaptopyridine and 15.24 g (60 mmol) of N-(2-bromoethyl)phthalimide in 200 ml of ethanol and stirred at room temperature for 24 hours. The mixture was heated under reflux for 2 hours. The solvent was distilled off chloroform was added to the residue, and the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexane=1:2) to obtain 8.00 g of the desired compound (46.9%, colorless crystals).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1>>[NH2:6][C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1
Reactant: CC(C)(N)CN
Reactant: N#Cc1ccc(Cl)nc1
Product: CC(C)(N)CNc1ccc(C#N)cn1
Temperature: 120 °C

Procedure:
A mixture of 1,2-diamino-2-methylpropane(3.14 mL, 30 mmol), and 6-chloronicotinonitrile (2.77 g, 20 mmol) were heated to 120° C. for 2 days. The reaction mixture was filtered, and the inorganic salt was rinsed with EtOAc. The filtrate was concentrated under reduced pressure to provide the titled compound as a pale yellow solid. MS (DCI) m/z 191 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([NH2:12])[N:6]=1)=[O:4].[F:13][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([F:13])=[CH:9][C:8]([Br:11])=[C:7]([NH2:12])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)c(N)n1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COC(=O)c1nc(N)c(Br)cc1F
Yield: 9.8 %

Procedure:
A mixture of 6-amino-5-bromo-pyridine-2-carboxylic acid methyl ester (19.8 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™), (34.3 g) in acetonitrile (340 ml) under argon was heated to 40° C. for 1 hour, 60° C. for 1 hour and then 80° C. overnight. After partitioning between EtOAc and water (500 ml each) the aqueous fraction was re-extracted with EtOAc (300 ml) and the combined organic solution dried with MgSO4 and evaporated. Chromatography (20% then 30% EtOAc in hexane) afforded the product (2.09 g).
Reaction SMILES: [NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)=O.O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:14]=1
Reactant: Nc1c(NCCCOc2cccc(C=O)c2)c(=O)c1=O
Reactant: C1CCNCC1
Solvent: O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: Nc1c(NCCCOc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Temperature: 65 °C
Yield: 62.8 %

Procedure:
A suspension of 1-amino-2-[3-(3-formylphenoxy)propylamino]-1-cyclobutene-3,4-dione (6.0 g, 21.8 mmole) in 150 mL of toluene was treated with piperidine (4.3 mL, 3.7 g, 43.6 mmole) and the mixture was heated to 65° C., and then cooled to about 30° C. Formic acid (2.2 mL of 95% aqueous formic acid containing 2.5 g formic acid, 55.4 mmole) was added. The mixture was heated to reflux temperature and the water formed was collected by azeotropic distillation. When the distillate became clear and gas evolution had ceased (about 30 minutes at reflux), the mixture was cooled and the solids were collected by filtration, washed with toluene, methanol and dried to yield 4.7 g (62.8%) of the title compound; mp=223°-228° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>CN(C)C=O.C(OCC)(=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>[CH:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1)=[CH2:14]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)OC)c(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask, which was purged and maintained with a nitrogen atmosphere, was added a solution of methyl 4-bromo-2-methylbenzoate (compound 152.1, 14.0 g, 61.1 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL). Tributyl(ethenyl)stannane (29.3 g, 92.4 mmol, 2.00 equiv) and Pd(PPh3)4 (7.10 g, 6.14 mmol, 0.10 equiv) were added to the reaction. The resulting mixture was stirred overnight at 100° C. in an oil bath. After cooling to room temperature, the mixture was diluted with 400 mL of ethyl acetate. The organic layer was washed with 2×400 mL of NH4Cl (aq.) and 2×400 mL of brine, dried over anhydrous sodium sulfate, then concentrated in vacuo. The crude product was purified by CombiFlash with the following conditions (IntelFlash-1): mobile phase, petroleum ether/ethyl acetate=1:0 increasing to petroleum ether/ethyl acetate=100:1 within 20 min; Detector, UV 254 nm. This resulted in 6.81 g (63%) of methyl 4-ethenyl-2-methylbenzoate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>N1C=CC=CC=1>[C:8]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: Nc1ccccn1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1

Procedure:
A solution of 13.4 g. of 2-aminopyridine in 300 ml. of pyridine is treated with 31.0 g. of 4-acetylbenzenesulfonyl chloride and the solution is stirred at room temperature for 6 hours. The solution is poured into 1 l. of cold water and the resulting precipitate of 4-acetyl-N-(2-pyridyl)benzensulfonamide is collected by filtration, washed with water and dried; m.p. 201°-202° C. after crystallization from methanol.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6](O)=[CH:5][CH:4]=1)=[O:2].CI.[C:15](=O)([O-])[O-].[K+].[K+].CN(C)[CH:23]=[O:24]>>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:24][CH3:23])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:15])=[O:9])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CI
Product: COC(=O)c1cc(C=O)ccc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Formyl salicylic acid (2.0 g, 12.0 mmol), methyl iodide (1.5 mL, 25 mmol) and potassium carbonate (3.06 g, 22.2 mmol) were combined in dimethylformamide (15 mL). After stirring at room temperature for 16 h, the solvent was removed in vacuo and the crude product dissolved in ethyl acetate, washed with water (2×), brine (2×), dried over sodium sulfate, concentrated, and purified by column chromatography to afford 1.85 g (79%). 1H-NMR (CDCl3, 500 MHz) δ 9.91 (s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.02 (dd, J=8.5, 2.5 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H). Mass spec.: 195.05 (MH)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:15]=2[OH:16])[N:12]=[CH:11][N:10]=[C:9]3[NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[C:19]=2[F:26])[CH2:2]1.ClC1C(F)=C(NC2C3C(=[CH:41][C:42](OC)=[C:43]([O:46][C@H]4CCNC4)C=3)N=CN=2)C=C(F)C=1>>[Cl:25][C:20]1[C:19]([F:26])=[C:18]([NH:17][C:9]2[C:8]3[C:13](=[CH:14][C:15]([OH:16])=[C:6]([O:5][CH:3]4[CH2:4][N:1]([C:43](=[O:46])[CH:42]=[CH2:41])[CH2:2]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COc1cc2ncnc(Nc3cc(F)cc(Cl)c3F)c2cc1O[C@H]1CCNC1
Reactant: Oc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CNC1
Product: C=CC(=O)N1CC(Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2O)C1
Yield: 25 %

Procedure:
The procedure of step 7) of Example 1 was repeated except for using the compound obtained in step 2) instead of N-(3-chloro-2,5-difluorophenyl)-7-methoxy-6-((3S)-pyrrolidin-3-yloxy)quinazolin-4-amine to obtain the title compound (20 mg, 25%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.[C:23]([C:27]1[CH:31]=[C:30]([NH2:32])[O:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24].CC([O-])(C)C.[K+]>O1CCOCC1>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[C:12]([CH:15]=3)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=2)[O:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: N#Cc1cc(-c2ccnc(F)c2)ccc1OC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(Nc2cc(-c3ccc(OC4CCOCC4)c(C#N)c3)ccn2)on1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 46 %

Procedure:
100 mg of 5-(2-fluoropyridin-4-yl)-2-(tetrahydropyran-4-yloxy)benzonitrile are suspended in 6 ml of dioxane in a 50 ml three-necked flask under N2, 52 mg of 3-tert-butylisoxazol-5-ylamine and 79 mg of KOtBu are added. The yellow solution is stirred at 80° C. for 2.5 h. For work-up, the reaction mixture is evaporated in a rotary evaporator, the residue is taken up in ethyl acetate and water and extracted. The collected organic phases are dried, filtered and evaporated. The crude product is purified by preparative HPLC, giving the desired product in 46% yield; HPLC-MS Rt. [min] 2.556; HPLC-MS [M+H] 419;
Reaction SMILES: [CH:1](O)=[O:2].[C:4]([O:7][C:8](=[O:10])C)(=[O:6])[CH3:5].C(N(C(C)C)CC)(C)C.[O:20]1[CH2:24][CH2:23][O:22][CH:21]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[C:34]([N+:39]([O-:41])=[O:40])[CH:33]=2)=[C:27]([O:42][CH3:43])[CH:26]=1.C(OC=O)(=O)C>C(OCC)(=O)C.O1CCCC1>[C:4]([O:7][CH:8]=[O:10])(=[O:6])[CH3:5].[O:20]1[CH2:24][CH2:23][O:22][CH:21]1[C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:38]=[CH:37][C:35]([NH:36][CH:1]=[O:2])=[C:34]([N+:39]([O-:41])=[O:40])[CH:33]=2)=[C:27]([O:42][CH3:43])[CH:26]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C2OCCO2)ccc1Oc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=CO
Agent: CC(=O)OC=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C2OCCO2)ccc1Oc1ccc(NC=O)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
Formic acetic anhydride was prepared by adding 96% formic acid (0.702 ml, 18.3 mmol) to acetic anhydride (0.863 ml, 9.1 mmol) and stirring for 30 minutes. A tetrahydrofuran solution of diisopropylethylamine (3.2 ml, 18.3 mmol) and 4-{[4-(1,3-dioxolan-2-yl)-2-(methyloxy) phenyl]oxy}-2-nitroaniline (2.53 g, 7.62 mmol) was added to the formic acetic anhydride. The reaction was stirred for approximately 18 hours. The reaction mixture was diluted with ethyl acetate and washed with 1N NaOH. The organic layers were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give (4-{[4-(1,3-dioxolan-2-yl)-2-(methyloxy)phenyl]oxy}-2-nitrophenyl) formamide. (M+1) 360.8, 2.31 min (LC/MS method B)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:41][CH2:40][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)=[O:29]
Reactant: COc1ccc(CCN)cc1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CCNC(=O)CN2CCc3cc(OC)c(OC)cc3C2Cc2ccc(OC)c(OC)c2)cc1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 4-methoxyphenylethylamine
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:40])[N:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[CH2:25][CH2:26][CH2:27][N:28]2[N:32]=[N:31][CH:30]=[N:29]2)[CH:20]=[C:19]([Cl:41])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:41][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])[CH2:25][CH2:26][CH2:27][N:28]1[N:32]=[N:31][CH:30]=[N:29]1)=[O:40]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCn2ncnn2)c2ccccc2F)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCn1ncnn1)c1ccccc1F
Yield: 87.6 %

Procedure:
A solution of {2-[3-chloro-5-(2-fluorophenyl-(3-tetrazol-2-yl-propyl)-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.048 g) in trifluoroacetic acid (0.5 ml) and dichloromethane (0.5 ml) was stirred at room temperature for 1 h then concentrated under vacuum. The residue was purified by flash chromatography, eluting with dichloromethane:methanol:ammonia (95:5:0.5 then 90:10:1 v/v/v), to give the title compound as an off-white foam (0.035 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].C(N(CC)CC)C.[CH2:24]([O:26][C:27](Cl)=[O:28])[CH3:25]>ClCCl>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:27]([O:26][CH2:24][CH3:25])=[O:28])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 48 h

Procedure:
To trans-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (1.09 g) and triethylamine (0.77 ml) in dichloromethane (20 ml), cooled in an ice bath, was added ethylchloroformate (0.67 ml). The mixture was allowed to attain room temperature and stirred for 2 days. The reaction mixture was washed with water and dried over anhydrous magnesium sulphate. Filtration and evaporation and chromatography (chromatotron, gradient elution: 10-30% Ethyl acetate-pentate) gave one fraction (456 mg) which was recrystallised from ethyl acetate-pentane to give the compound of this example (319 mg); mp 147°-148° C.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][S:16][CH2:15][CH2:14]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][S:16][CH2:17][CH2:18]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(C3CCSCC3)sc2CC)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1sc(C2CCSCC2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a mixture of ethyl 3-({[4-({cyclohexyl[2-ethyl-5-(tetrahydro-2H-thiopyran-4-yl)thiophen-3-yl]methyl}amino)phenyl]carbonyl}amino)propanoate (338 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (296 mg, 93%) as a white solid.
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:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23].[NH4+].[N:25]#[C:26][S-:27].BrBr>CC(O)=O>[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[C:17]([F:23])=[CH:18][C:19]2[N:22]=[C:26]([NH2:25])[S:27][C:20]=2[CH:21]=1
Reactant: N#C[S-]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc2nccc(Oc3cc4sc(N)nc4cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylamine (1.00 g, 3.18 mmol) was dissolved in AcOH (8.0 ml), to which was added NH4SCN (486 mg, 6.38 mmol) and the mixture cooled in an ice bath. Br2 (0.33 ml, 6.42 mmol) in AcOH (0.33 ml) was added dropwise with stirring. After addition was complete, the reaction mixture was stirred at room temperature. After one hour, more NH4SCN (1.0 g, 13.1 mmol) was added, followed by more Br2 (0.33 ml, 6.42 mmol) in AcOH (0.33 ml), dropwise with stirring. The reaction mixture was then heated to reflux for several minutes. Upon cooling to room temperature, solids were filtered and washed with AcOH, followed by H2O. The volume of the filtrate was reduced in vacuo and the pH adjusted to pH 9-10 with 1.0N NaOH. The resulting solids were filtered, washed with H2O, and dried under high vacuum to give 6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine (568 mg, 48%). 1H-NMR (400 MHz, DMSO): 8.45 (d, 1H), 7.82 (d, 1H), 7.73 (br s, 2H), 7.53 (s, 1H), 7.38 (m, 2H), 6.44 (d, 1H), 3.94 (s, 6H). LC/MS Calcd for [M+H]+ 372.1, found 372.2
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][CH2:30][CH2:31][C:32]#[N:33]>C(OCC)(=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:33][CH2:32][CH2:31][C:30]#[N:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#CCCN
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCC(=O)NCCC#N
Reaction time: 0.08 h

Procedure:
N-t-Butoxycarbonyl-β-alanine (5.8 mmol) in ethyl acetate (30 mL) and methylene chloride (7.5 mL) is cooled under nitrogen to 0° with an ice bath and treated with N-methylmorpholine (5.8 mmol). Isobutyl chloroformate (5.8 mmol) is added dropwise. After 5 minutes of stirring, 3-aminopropionitrile (6.4 mmol) in methylene chloride (5.0 mL) is added slowly. Stirring is continued for 1 hour at 0°, then for 4 hours at room temperature. Ethyl acetate (30 mL) is added and the solution is successively washed with cold water (100 ml), saturated sodium bicarbonate (10 mL) and water (10 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-(t-butoxycarbonylamino)-N-(2-cyanoethyl)propionamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6].[OH:24]O.[OH-].[Na+].O>CS(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]([NH2:6])=[O:24]
Reactant: OO
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound (158a) (0.100 g) was dissolved in DMSO (1.2 mL). A hydrogen peroxide solution (30 wt %) (0.053 mL) and a 4 mol % aqueous sodium hydroxide solution (0.233 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (158b) (0.090 g).