Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH2:11])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].[Cl:17][CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:31][O:32][CH3:33])[C:28](Cl)=[O:29])[N:26]=1)=[O:20].O>O1CCCC1>[C:1]([O:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH:11][C:28](=[O:29])[C:27]([C:25]1[N:26]=[C:22]([NH:21][C:19](=[O:20])[CH2:18][Cl:17])[S:23][CH:24]=1)=[N:31][O:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1NC(=O)[C@H]1N
Reactant: CON=C(C(=O)Cl)c1csc(NC(=O)CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1COC(C)=O)c1csc(NC(=O)CCl)n1

Procedure:
Under ice-cooling and stirring, 12 ml of an aqueous solution containing 632 mg of cis-4-acetoxymethyl-3-amino-2-oxoazetidine and 1.122 g of sodium hydrogen carbonate is added to a suspension of 2.36 of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride (syn-isomer) in 20 ml of tetrahydrofuran. The mixture is stirred for 2 hours at room temperature and the solvent is then distilled off in vacuo to leave the residue, which solidifies. Water is added to the solidified residue, followed by filtration. The collected crystals are washed successively with an aqueous sodium hydrogen carbonate solution, water and ether and dried to give cis-4-acetoxymethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine (syn-isomer), m.p. 180°-190° C. (dec.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=[O:11])[CH:3]=[CH:2]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:13]([O:11][C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1cccc2cc[nH]c12
Yield: 83.4 %

Procedure:
A solution of 0.68 g (4.2 mmol) of indole-7-carboxylic acid, 0.9 g (8.4 mmol) of benzylalcohol 1.03 g (8.4 mmol) of DMAP and 1.6 g (8.4 mmol) of 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (Aldrich) in 30 mL of CH2Cl2 was stirred at rt for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, hexanes:ethyl acetate 30:1) to give 0.88 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH:10]([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:19])[CH:13]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:29](Br)[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[CH2:33]([O:32][C:30]([CH:29]1[O:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:10]([N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:8][CH3:9])[CH3:20])=[CH:13][C:14]=2[O:19]1)=[O:31])[CH3:34]
Reactant: CCOC(=O)C(Br)Br
Reactant: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2ccc(CC(C)N(CC)C(=O)OC(C)(C)C)cc2O1
Temperature: 120 °C
Yield: 79.1 %

Procedure:
To 2 g (6.7 mmol) of 2C was added 40 mL of anhydrous DMF followed by 3.5 g (25 mmol) of anhydrous K2CO3, 5 g of 3 A° molecular sieves and 3.2 mL (25 mmol) of ethyl dibromoacetate. The reaction mixture was heated at 120° C. for 3 hours under argon atmosphere and then concentrated under reduced pressure. To the residue 75 mL of ethyl acetate were added and filtered. To the filtrate 75 mL of water were added and transferred to a separatory funnel. The organic layer was separated, and the aqueous layer was extracted with 5×75 mL of ethyl acetate. All the organic layers were combined, dried (anhydrous Na2SO4), and concentrated to dryness. The residue was purified by silica gel column chromatography using 10% ethyl acetate in hexane to give 954 mg (5.3 mmol, 37%) of 2D as a colorless gum (M+Na, 402).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[F:10][CH2:11][CH:12](O)[CH2:13][F:14]>>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:12]([CH2:13][F:14])[CH2:11][F:10])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: OC(CF)CF
Reactant: Cc1ncc(Br)cc1O
Product: Cc1ncc(Br)cc1OC(CF)CF

Procedure:
The title compound was synthesized in a similar manner as described for stage 58.1.2 using 5-bromo-2-methyl-pyridin-3-ol (stage 189.1.2, 2.234 mmol) and 1,3-difluoro-2-propanol (Aldrich, Buchs, Switzerland, 2.68 mmol) to give the title compound as a yellow oil. (HPLC: tR 2.41 min (Method A); M+H=266, 268 MS-ES).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[C:21]1([C@H:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCO>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][NH:29][C@@H:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:28])([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN[C@H](C)c1ccccc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 120 h
Yield: 117 %

Procedure:
To a stirred solution of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO04/063163, 600 mg, 2.05 mmol) in anhydrous EtOH (3 mL) was added (R)-(+)-1-phenylethylamine (1.31 mL, 10.3 mmol). The reaction mixture was then stirred and heated at 50° C. under nitrogen overnight and then for 5 days, cooled to room temperature and evaporated in vacuo. The residue was applied to a 70 g silica SPE cartridge and eluted with 0.5% NH3 in toluene. The appropriate fractions were combined and evaporated in vacuo to give a colourless oil (991.4 mg). 710 mg of this oil was separated by chiral HPC on a 2 inch×15 cm Chiralpak AD column eluted with 25% acetonitrile/0.25M ammonium phosphate (pH 4.9) with a flow rate of 70 mL/min to give Intermediate 9 (2S isomer, 230 mg) after 17.5 min and Intermediate 10 (2R isomer, 200 mg) after 24.8 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([Br:15])[CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cc1ccc(-n2cc(Br)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-methylphenyl)-2-cyanopyrrole (1.274 g) in tetrahydrofuran (25 ml) is added N-bromosuccinimide (1.776 g) in several portions at room temperature. After being stirred for 3 hours at ambient temperature, the mixture is concentrated in vacuo. The residue is treated with diethyl ether. The precipitates are removed by filtration and washed with a small amount of diethyl ether. The filtrates are concentrated in vacuo to give an oily residue, which is purified by silicagel column chromatography (elution by 40% methylene chloride in n-hexane) to yield 1-(4-methylphenyl)-4-bromo-2-cyanopyrrole as a solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:14]3[N:15]=[CH:16][N:17]=[C:13]3[C:12]([NH:18][C:19]3[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[CH:21][CH:20]=3)=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.Cl.[NH+]1C=CC=CC=1>O>[O:2]=[C:3]1[CH:8]=[C:7]([C:9]2[N:14]3[N:15]=[CH:16][N:17]=[C:13]3[C:12]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:24])=[CH:33][CH:34]=3)=[N:11][CH:10]=2)[CH:6]=[CH:5][NH:4]1
Reactant: COc1cc(-c2cnc(Nc3ccc(C(=O)NCc4cccnc4)cc3)c3ncnn23)ccn1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: O=C(NCc1cccnc1)c1ccc(Nc2ncc(-c3cc[nH]c(=O)c3)n3ncnc23)cc1
Temperature: 150 °C

Procedure:
A mixture of 4-[5-(2-methoxy-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-N-pyridin-3-ylmethyl-benzamide (71.5 mg, 0.16 mmol) and pyridinium hydrochloride (91 mg, 0.79 mmol) in water (0.5 mL) in a sealed tube is heated at 150° C. for 25 minutes. After this time the solvent is removed in vacuo. The residue is chromatographed on silica gel, eluting with DCM followed by 98:2 and 90:10 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated. The title compound is isolated as a yellow solid (34.5 mg, 49%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:10]2=[O:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].CO.[OH-].[Na+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:10]2=[O:28])=[CH:5][C:4]=1[C:29]([F:30])([F:32])[F:31])#[N:2]
Reactant: CCOC(=O)CCCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C12CCOCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(N2C(=O)N(CCCC(=O)O)C3(CCOCC3)C2=O)cc1C(F)(F)F
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
522 mg of the product of Example 6 and 20 ml of methanol were mixed together and the solution was heated to 30° C., then returned to ambient temperatures 2 ml of 2N sodium hydroxide were added and the reaction medium stood for 4 hours and 30 minutes, then was poured into 30 ml of water and adjusted to pH 2-3. Extraction was carried out 3 times with ethyl acetate and the organic phase was washed with water, then with salt water, dried and purified on silica with methylene chloride-methanol: 9-1 as eluant. Then, solidification was carried out by trituration in 0.2 ml of isopropanol and 5 ml of ether to obtain 345 mg of the expected product (white crystals) melting at 151°-152° C.
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[CH2:5]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17]O)[CH2:6][CH2:7][CH3:8].[CH2:19]([N:23]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][OH:26])[CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:19]([N:23]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][OH:26])[CH2:20][CH2:21][CH3:22].[B:1]([O-:4])([O-:3])[O:2][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OB(O)O
Reactant: CCCCOCCOCCOCCO
Agent: CCCCN(CCO)CCCC
Solvent: Cc1ccccc1
Product: CCCCOCCOCCOCCOB([O-])[O-]
Reaction time: 8 h
Yield: 128.2 %

Procedure:
N,N-dibutylethanolamine/triethylene glycol monobutyl ether borate was prepared as follows. Boric acid (10.3 grams), triethylene glycol monobutyl ether (Fluka, 64.1 grams), and N,N-dibutylethanolamine (28.9 grams) were added to a 250 milliliter flask. One hundred fifty milliliters of toluene was then added. The reaction was allowed to proceed overnight at 110° C., and the byproduct water (˜9 grams) was continuously removed from the reaction by azeotropic distillation. The final solution was evaporated to remove toluene under vacuum, and a brownish liquid product (˜90 grams) of N,N-dibutylethanolamine/triethylene glycol monobutyl ether borate was obtained.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[S:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]([C:16]1[CH:25]=[CH:24][C:23]2[NH:22][C:21](=[O:26])[C:20]3[NH:27][CH:28]=[CH:29][C:19]=3[C:18]=2[CH:17]=1)=O.[CH2:30]([C:32]([O-:34])=[O:33])[CH3:31]>C(O)C>[O:26]=[C:21]1[C:20]2[NH:27][CH:28]=[CH:29][C:19]=2[C:18]2[CH:17]=[C:16]([C:14]3[N:11]=[C:9]([NH:8][NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:10][CH:13]=3)[CH:25]=[CH:24][C:23]=2[NH:22]1.[CH2:30]([C:32]([O-:34])=[O:33])[CH3:31]
Reactant: NC(=S)NNc1ccccc1
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CCO
Product: O=c1[nH]c2ccc(-c3csc(NNc4ccccc4)n3)cc2c2cc[nH]c12
Temperature: 90 °C
Reaction time: 6 h
Yield: 42.1 %

Procedure:
66 mg (1.2 mmol) of 1-phenylthiosemicarbazide is added to a suspension of 124 mg (0.33 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3.5 mL of ethanol. The mixture is stirred at 90° C. for 6 hours then the mixture is cooled to room temperature. The solvent is evaporated, then the product is purified by preparative LCMS. After drying, 62 mg (42%) of 4-oxo-8-[2-(N′-phenyl-hydrazino)-thiazol-4-yl]-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C:41]([OH:43])=[O:42])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCCC1.C1(C)C=CC=CC=1.C(O)C.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>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41]([OH:43])=[O:42])=[CH:36][CH:35]=3)=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(-c3ccc(CC(=O)O)cc3)cc2)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
A mixture of 1-[(4-bromophenyl)carbonyl]-4-(2-tert-butylphenyl)piperazine (1.0 g, 2.49 mmol), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetic acid (0.653 g, 2.49 mmol), 2 M sodium carbonate solution (3 mL, 6.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.150 g, 0.13 mmol) in tetrahydrofuran (5 mL) and toluene (20 mL) was stirred at 120° C. for 16 h. 6 M hydrochloric acid solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a solid. The solid was dissolved in ethanol-ethyl acetate and recrystallized to obtain a solid (0.3 g, 26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.ClCCl.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][O:10][C:21](=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(CO)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc(COC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-methoxy-phenyl)-methanol (14.15 g, 102.4 mmol) and triethylamine (32.8 mL, 235.6 mmol) in dry dichloromethane (45 mL) dimethylaminopyridine (1.3 g, 10.2 mmol) and acetic anhydride (11.1 mL, 118.0 mmol) was added at 0° C. and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with 1N HCl solution. The organic solution was dried over Na2SO4, evaporated in vacuo and purified by column chromatography (ethyl acetate:hexane; 5:95) to give the acetic acid 3-methoxy-benzyl ester as a slightly yellow oil (17.84 g, 96%). 1H NMR (CDCl3, 400 MHz) 2.08 (s, 3H), 3.78 (s, 3H), 5.06 (s, 2H), 6.85 (d, J=8.0 Hz, 1H), 6.89 (s, 1H), 6.92 (d, J=8.0 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 13C NMR (CDCl3, 100 MHz) 20.6, 54.8, 65.7, 113.30, 113.32, 120.0, 129.2, 137.1, 159.4, 170.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:20][CH2:19]2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]
Reactant: CCN(CC)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: CCN(CC)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1

Procedure:
Following general procedure D, {6-bromo-4-[trans-4-(diethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (31 mg, 0.070 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.015 mmol) to afford the desired product (19.7 mg, 54%) as an orange-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.15 (s, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.04 (dd, J=8.7, 1.9 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.31 (d, J=2.1 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 4.20 (s, 1H), 3.99 (s, 3H), 3.12 (q, J=7.2 Hz, 4H), 2.89-2.80 (m, 1H), 2.41 (d, J=10.4 Hz, 2H), 2.15 (d, J=9.8 Hz, 2H), 1.82-1.62 (m, 4H), 1.30 (t, J=7.3 Hz, 6H), 1.23-1.16 (m, 2H), 1.15-1.04 (m, 2H); ESI MS m/z 522 [C30H36ClN3O3+H]+; HPLC 98.5% (AUC), tR=11.05 min.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: Nc1ccccn1
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Product: CC(=O)N1c2ccc(C(=O)Nc3ccccn3)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 20.6 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 82 mg of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid and 28 mg of 2-aminopyridine. Thus, 20 mg (21%) of the title compound was obtained as a yellow amorphous substance.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:51]([NH:50][C:44]1[N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:47]([F:48])=[CH:46][C:45]=1[F:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)Nc1nc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 15 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 4.20 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 3.30 g of 2-amino-6-(t-butylamino)-3,5-difluoropyridine. The solution was concentrated under reduced pressure to obtain orange-colored solid residue. To this residue were added 4.0 g of anhydrous potassium carbonate and 8 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 10 minutes and allowed to cool. The solution was separated by adding 50 ml of chloroform and 500 ml of distilled water, and the chloroform layer was washed twice with 500 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 4.67 g of the title compound as a colorless powder.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].[CH3:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2Cl)=[O:15])=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[CH:9][N:8]=1.CN(C=O)C>O>[CH3:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[S:4][CH2:2][CH3:3])=[O:15])=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[CH:9][N:8]=1
Reactant: CCS
Reactant: CNc1ncc(C(F)(F)F)cc1NC(=O)c1cnccc1Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
289 mg of ethyl mercaptan sodium salt (80%) was added to a mixture of 828 mg of 4-chloropyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide and 4 ml of DMF was added under ice cooling, then the mixture was heated to room temperature, and stirred for 3 hours. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 700 mg of 4-ethylsulfanylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 4-Ethylsulfanylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH:28]=[O:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[CH:24][N:23]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO.O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH2:28][OH:29])=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[CH:24][N:23]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(CNc1ncnc(N2CCC(c3ccc4c(n3)NCCC4)CC2)c1C=O)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C(CNc1ncnc(N2CCC(c3ccc4c(n3)NCCC4)CC2)c1CO)NC(=O)OCc1ccccc1
Yield: 47.1 %

Procedure:
340 mg (0.55 mmole) of tert-butyl 2-benzyloxycarbonylamino-3-{5-formyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in 50 ml of methanol with 350 mg (9.2 mmoles) of sodium borohydride is stirred at ambient temperature for 2 hours. Then 100 ml of a saturated solution of ammonium chloride is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue obtained is taken up in a mixture of water and ethyl acetate. The organic phase is dried over magnesium sulphate then the solvent is evaporated off under reduced pressure (2 kPa). The crude product obtained is chromatographed on silica gel eluting with a gradient of methylene chloride and ethyl acetate (100-0 to 0-100). 160 mg of expected product is obtained in the form of a yellow oil.