Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: Brc1nccs1
Solvent: O
Product: c1csc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 61 h
Yield: 75.3 %

Procedure:
A solution of 2-bromothiazole (356 μL, 4.00 mmol) in morpholine (2.09 mL, 24.0 mmol) was warmed at 100° C. in a sealed tube. After 61 hours, the mixture was cooled to room temperature, diluted with 20 mL of water, and extracted with three 30 mL portions of diethyl ether. The combined organic layers were washed with five 30 mL portions of water, 30 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed over SiO2 (20-100% ethyl acetate in hexanes, gradient) to afford 513 mg (75%) of 4-thiazol-2-yl-morpholine.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH2:35][CH3:36])[C:27]([CH:29]2[CH2:31][CH:30]2[C:32](Cl)=[O:33])=[O:28])=[CH:22][CH:21]=1)([O-:19])=[O:18].C(Cl)(=O)C(Cl)=O.S(Cl)(Cl)=O>C(Cl)Cl>[CH2:35]([N:26]([C:23]1[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[C:27]([CH:29]1[CH2:31][CH:30]1[C:32]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:33])=[O:28])[CH3:36]
Reactant: CCCCCCCCNCc1ccccc1
Reactant: CCN(C(=O)C1CC1C(=O)Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCN(Cc1ccccc1)C(=O)C1CC1C(=O)N(CC)c1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 32 react N-octylbenzenemethanamine with 2-[[(4-nitrophenyl)(ethyl)amino]carbonyl]cyclopropane-1-carbonyl chloride (prepared from the acid and oxalyl chloride or thionyl chloride) in methylene chloride to obtain the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=O)[CH3:10].[OH-:12].[K+].O.NN>C(O)CO>[OH:12][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][CH3:10]
Reactant: CC(=O)c1cccn1CCBr
Reactant: [OH-]
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: CCc1cccn1CCO
Temperature: 200 °C
Reaction time: 1.5 h

Procedure:
A mixture containing 1-(2-bromoethyl)-2-acetyl-1H-pyrrole (82 g), ethylene glycol (45 mL), 85% potassium hydroxide pellets (8.91 g) and 80% hydrazine hydrate (6.76 mL) was stirred at 200° C. for about 1.5 hr along with simultaneous distillation of volatile materials. The product obtained was extracted with ethyl acetate (2×100 mL). The ethyl acetate layer was washed with water (100 mL), dried over sodium sulfate, filtered and evaporated. The crude product obtained was purified by column chromatography (silica gel 100-200), using ethyl acetate:pet. ether (8:2) as an eluent to obtain 2.2 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[Li+].Cl>CO.C1COCC1.O>[OH:24][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])/[CH:17]=[CH:16]/[C@H:11]1[CH2:12][CH2:13][C:14](=[O:15])[N:10]1[CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]([OH:25])=[O:2]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCCCOCC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCCCOCC(=O)O
Temperature: 45 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
To a solution of {4-[(R)-2-((E)-(S)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-butoxy}-acetic acid methyl ester (0.14 g, 0.4 mmol) in a mixture of 2 mL of methanol and 2 mL THF at room temperature under a nitrogen atmosphere was added an aqueous solution of lithium hydroxide (0.066 g, 1.6 mmol) in 1 mL of water. The reaction was stirred at 45° C. overnight, cooled to room temperature and treated with aqueous hydrochloric acid (1 M) until acidic. The residue was diluted with water (10 mL) and extracted with ethyl acetate. The organic solution was dried (brine, Na2SO4), evaporated and purified by chromatography to yield 28 mg of {4-[(R)-2-((E)-(S)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-butoxy}-acetic acid; ESMS: m/z (M+) 341.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:6]([C:11]2[CH:12]=[C:13]([Cl:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)[C:7](=[O:10])[C:8]=1O)(=O)[CH3:2].Cl.[CH:28]([NH:31][NH2:32])([CH3:30])[CH3:29]>>[Cl:19][C:13]1[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=[C:11]([N:6]2[CH:5]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:4]3[C:8](=[N:32][N:31]([CH:28]([CH3:30])[CH3:29])[C:1]=3[CH3:2])[C:7]2=[O:10])[CH:12]=1
Reactant: CC(C)NN
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Agent: Cl
Product: Cc1c2c(nn1C(C)C)C(=O)N(c1cc(Cl)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 58 using 5-(3-acetyl-2-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-chloro-1-methyl-pyridin-2(1H)-one (Step 58.1) and isopropylhydrazine hydrochloride. The crude material was purified by preparative achiral SFC (column 4-Ethyl-pyridine, gradient 17-22% in 6 min_total 11 min). tR: 4.45 min (HPLC 1); tR: 1.01 min (LC-MS 2); ESI-MS: 431 [M+H]+ (LC-MS 2); Rf=0.31 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.42 (m, 6H) 2.07 (s, 3H) 3.43 (s, 3H) 4.52-4.62 (m, 1H) 6.12 (s, 1H) 7.23-7.30 (m, 2H) 7.34-7.40 (m, 2H) 7.87-7.90 (m, 1H) 7.90-7.93 (m, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][NH:27]2)=[CH:23][CH:22]=1>CC(O)CCC>[ClH:2].[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([NH:20][C:3]3[C:12]4[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=4)[N:6]=[CH:5][CH:4]=3)[CH:29]=2)[CH:25]=[N:26]1
Reactant: COCCOc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1ccc2cn[nH]c2c1
Agent: Cl
Solvent: CCCC(C)O
Product: COCCOc1cc2nccc(Nc3ccc4cn[nH]c4c3)c2cc1OC
Yield: 54.8 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (300 mg, 1 mmol) (prepared as described for the starting material in Example 5), and 6-aminoindazole (130 mg, 0.97 mmol) in 2-pentanol (10 ml) was heated at reflux for 3 hours. The precipitate was collected by filtration, washed with acetone and dried under vacuum. The residue was purified by reverse phase column chromatography eluting with methanol/water containing 1% acetic acid (40/60). Concentrated hydrochloric acid (5 drops) was added to the combined fractions of the product and the volatiles were removed by evaporation to give 4-(1H-indazol-6-ylamino)-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (213 mg, 54%).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH2:19])=[O:18])=[O:14])[CH2:11][CH3:12])=[O:8].[H][H]>C(O)(=O)C.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH2:19])=[O:18])=[O:14])[CH2:11][CH3:12])=[O:8]
Reactant: CC[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 91.3 %

Procedure:
2.67 g (6 mmoles) of Z-Glp-Abu-Pro-NH2 are dissolved in 100 ml of acetic acid. 0.5 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the residue is triturated with ether. The resulting 1.82 g of amorphous crude product are dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 1.70 g (91%) of Glp-Abu-Pro-NH2 are obtained; Rf4 =0.24, [α]D25 =-102.5° (c=1%, in acetic acid).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CC(=O)C=C1)CCC.C(Cl)([Cl:23])=O>C1(C)C(C)=CC=CC=1>[C:1]([Cl:23])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(O)c1ccccc1
Agent: CCCCn1ccc(=O)cc1
Solvent: Cc1ccccc1C
Product: O=C(Cl)c1ccccc1
Yield: 96 %

Procedure:
The procedure described in Example 1 was used and was applied to a solution of 1 mol of benzoic acid in 140 g of xylene. The reaction was carried out in the presence of 10 mmols of N-butyl-4-pyridone. 120 g of phosgene were introduced in the course of 2 hours 40 minutes. The yield obtained after distillation is 98.5%. Infra-red spectrometry did not reveal any trace of benzoic anhydride in the residue. The latter was recycled and a further batch of one mol of benzoic acid was introduced into the reactor. 120 g of phosgene are introduced in the course of 3 hours and the usual cycle is followed. A yield of 96% of benzoyl chloride was obtained after distillation. The residue still showed no traces of anhydride in infra-red spectrometry.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[Cl:15]Cl>C(Cl)(Cl)Cl>[Cl:15][C:5]1[C:6]([OH:11])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]([OH:1])=[C:3]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: ClCl
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Solvent: ClC(Cl)Cl
Product: CCCc1c(O)c(Cl)cc(C(C)=O)c1O
Reaction time: 2.5 h
Yield: 51 %

Procedure:
To a solution of 5.0 g (0.026 mol) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone in 125 ml of chloroform was added 32.3 ml of (0.030 mol) 0.94M chlorine in chloroform dropwise at 25°. The mixture was stirred at 25° for 2.5 hours. The solvent was removed in vacuo and the residue was extracted with hot hexane. The hexane extract was boiled down to 100 ml and allowed to crystallize. Filtration gave 3.0 g, melting point 96°. (51% yield) of 1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone.
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[C:11]([C:25]([F:28])([F:27])[F:26])[CH:10]=3)=[N:5][N:4]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:3]1=[O:37].[CH3:38][C:39]1([C:50](OS(C(F)(F)F)(=O)=O)=[CH2:51])[CH2:42][N:41]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40]1.C(OC(N1CC(C)(C(O)=O)C1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:46]([O:45][C:43]([N:41]1[CH2:42][C:39]([CH3:38])([C:50]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][C:11]=2[C:25]([F:26])([F:28])[F:27])[O:8][CH2:7][C:6]2[N:15]3[CH:2]([CH3:1])[C:3](=[O:37])[N:4]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[N:5]=2)=[CH2:51])[CH2:40]1)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: C=C(OS(=O)(=O)C(F)(F)F)C1(C)CN(C(=O)OC(C)(C)C)C1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(B4OC(C)(C)C(C)(C)O4)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)OC(=O)N1CC(C)(C(=O)O)C1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1cc2c(cc1C(F)(F)F)OCC1=NN(COCC[Si](C)(C)C)C(=O)C(C)N12)C1(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
A mixture of 4-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #107, Step A, 4.87 g, 6.279 mmol), tert-butyl 3-methyl-3-(1-(trifluoromethylsulfonyloxy)vinyl)azetidine-1-carboxylate (Prepared from 1-(tert-butoxycarbonyl)-3-methylazetidine-3-carboxylic acid using the procedure detailed in Preparation #4, Steps A-C, 2.168 g, 6.279 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.513 g, 0.628 mmol) and K2CO3 (1.735 g, 12.554 mmol) in dioxane (48 mL) and water (8 mL) was stirred at 90° C. for 3 h. The reaction mixture was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 0% to 20% EtOAc in petroleum ether) to give 3-methyl-3-{1-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-vinyl}-azetidine-1-carboxylic acid tert-butyl ester (1.214 g, 31%). LC/MS (Table 1, Method 27) Rt=1.481 min; MS m/z: 633 [M+Na]+.
Reaction SMILES: C1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]3)=[CH:11][C:10]=2[CH3:24])[NH2:8])CCCCC1.F[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:9]1([N:8]([CH2:7][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[N:16]3)=[CH:11][C:10]=2[CH3:24])[C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1C(N)C1CCCCC1
Reactant: COC(=O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of (+/−)-cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine (80.0 mg, 0.237 mmol) in N,N-dimethylformamide (3 mL) was added methyl 6-fluoronicotinate (55.2 mg, 0.356 mmol) and potassium carbonate (98.4 mg, 0.712 mmol). The reaction was heated to 110° C. and stirred overnight. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave (+/−)-methyl 6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinate (20 mg, 15%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.63 (s, 1H), 8.06 (s, 1H), 7.79-7.82 (m, 2H), 7.43 (s, 1H), 7.33-7.36 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.03 (d, J=8.8 Hz, 1H), 5.39 (d, J=6.8 Hz, 1H), 4.74 (m, 1H), 3.75 (s, 3H), 2.49 (s, 3H), 1.85-1.88 (m, 1H), 1.58-1.72 (m, 5H), 1.05-1.19 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([S:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][C:13]=2[Cl:23])[CH:3]=1.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([S:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][C:13]=2[Cl:23])[CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2[N+](=O)[O-])c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2N)c(Cl)c1

Procedure:
The product from step (ii) (0.80 g) and reduced iron powder (0.80 g) in glacial acetic acid (30 ml) was vigorously stirred at RT for 2 h. The mixture was filtered through celite, and the filtrate evaporated under reduced pressure to give a brown oil which was neutralised with 2M NaOH and extracted with ethyl acetate. The organics were dried, evaporated under reduced pressure and the residue purified by chromatography on silica eluting with isohexane/ethylacetate 2:1, yield 0.70 g.
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:20][CH:21]([F:25])[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[F:20][CH:21]([F:25])[C:22](=[O:23])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=CN1CCCCC1
Reactant: O=C(Cl)C(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Methyl 3-piperidin-1-ylacrylate (99%, 26.6 g, 155 mmol) and triethylamine (17.3 g, 171 mmol) were initially charged in toluene (300 ml) and cooled to −30° C. At this temperature, difluoroacetyl chloride (20 g, 171 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h, another 200 ml of toluene were added to keep the suspension stirrable and the mixture was then warmed to room temperature over a period of 1 hour. The reaction mixture was washed with deionized water (200 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. This gave methyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 37.6 g; purity according to quant. NMR: 82.2%; yield: 80.3%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.Cl.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH2:7][N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: CN1CCNCC1
Reactant: O=Cc1occc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2occc2Br)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.2 %

Procedure:
To a solution of 3-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol), 1-methylpiperazine dihydrochloride (986 mg, 5.71 mmol) and triethylamine (1.5 mL, 11.4 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.71 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (100 mL). The organic phase was washed with aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (570 mg, 78%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O-:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2].[Na+].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2]
Reactant: ClCCCc1ccncc1
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc([O-])c(C#N)cc34)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCc5ccncc5)c(C#N)cc34)cc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
The sodium 6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate (200 mg) synthesized in Example 87 was dissolved in dimethylformamide (4 ml), and then potassium carbonate (130 mg, 0.9400 mmol), potassium iodide (3 mg) and 1-chloro-3-(4-pyridyl)propane (80 mg, 0.5159 mmol) were added and the mixture was heated and stirred at 80° C. for 5 hours and 30 minutes. After allowing the mixture to stand and adding saturated saline, it was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system). The obtained crystals were suspended in ethanol, the suspension was diluted with diethyl ether, and the crystals were filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (60 mg) as light yellow crystals.
Reaction SMILES: CS(N)(=O)=O.[CH:6]1([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:40]1([C:43]2[C:44]([O:53][CH:54]3[CH2:59][CH2:58][CH2:57][C:56]([CH3:61])([CH3:60])[CH2:55]3)=[CH:45][C:46]([F:52])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[CH2:42][CH2:41]1>>[CH:40]1([C:43]2[C:44]([O:53][CH:54]3[CH2:59][CH2:58][CH2:57][C:56]([CH3:61])([CH3:60])[CH2:55]3)=[CH:45][C:46]([F:52])=[C:47]([CH:51]=2)[C:48]([NH:12][S:9]([CH:6]2[CH2:8][CH2:7]2)(=[O:11])=[O:10])=[O:49])[CH2:42][CH2:41]1
Reactant: CC1(C)CCCC(Oc2cc(F)c(C(=O)O)cc2C2CC2)C1
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: CC1(C)CCCC(Oc2cc(F)c(C(=O)NS(=O)(=O)C3CC3)cc2C2CC2)C1

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methane sulfonamide with cyclopropane sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzoic acid, the title compound was obtained as a white solid (0.07 g, 31%): 1H NMR (300 MHz, DMSO-d6) δ11.79 (s, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.03 (d, J=13.3 Hz, 1H), 4.67-4.58 (m, 1H), 3.11-3.03 (m, 1H), 2.06-1.95 (m, 2H), 1.76-1.70 (m, 1H), 1.65-1.54 (m, 2H), 1.37-1.17 (m, 4H), 1.13-1.08 (m, 4H), 0.98 (s, 3H), 0.97 (s, 3H), 0.90-0.84 (m, 2H), 0.68-0.63 (m, 2H); MS (ES+) m/z 410.0 (M+1).
Reaction SMILES: [C@H:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:7])([CH2:3][CH3:4])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C@H:1]([NH:5][C:6](=[O:7])[C:8]1[CH:27]=[CH:26][CH:25]=[C:10]([CH2:11][N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH:9]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)NC(=O)c1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](C)NC(=O)c1cccc(CN2CCNCC2)c1
Reaction time: 24 h
Yield: 95.4 %

Procedure:
To a stirred solution of (R)-tert-butyl 4-(3-(sec-butylcarbamoyl)benzyl)piperazine-1-carboxylate (5.33 mmol, 2 g) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred for 24 hours then was concentrated under reduced pressure. Purification by strong cation exchange column chromatography gave the title compound (1.4 g). MS (ESI) m/z 276.3 ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2C=CC=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>ClCCl>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][CH:48]([CH3:53])[CH3:49])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)N
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in dichloromethane (2 mL) were added HBTU (30 mg, 0.079 mmol) and isopropylamine (0.032 mL, 0.37 mmol). The mixture was stirred at r.t. overnight. Solvent was removed by rotovap. Separation by chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (22 mg, 51%). LC-MS m/z 563 (M+H)+.