Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[S:8]1(=[O:10])(=[O:9])[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH2:12][NH:11]1
Reactant: C=O
Reactant: Nc1cccnc1S(N)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=S1(=O)NCNc2cccnc21

Procedure:
A mixture of 1 g of 3-aminopyridine-2-sulfonamide (Preparation 1) and 0.23 g of paraformaldehyde (1.3 eq.) in 10 cm3 of isopropanol to which 10 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 1 to 2 hours. After cooling, the crystalline precipitate of the title compound is collected on a filter and washed with isopropanol. The product is recrystallized from hot water.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.C(Cl)Cl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:2][C@@H:3]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:26])=[CH:28][CH:29]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)C[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Prepared using General Procedure 7. A solution of (S)-methyl 3-amino-4-(4-hydroxyphenyl)butanoate hydrochloride (2.1 g, 8.7 mmol), 4-(tert-butyl)benzoic acid (1.6 g, 9.0 mmol) and DIEA (3.5 ml, 18.8 mmol) in DMF (20 mL) and DCM (20 mL) was treated with HATU (3.3 g, 8.5 mmol). After 1 h, the mixture was poured onto 1M HCl (100 mL) and extracted with EA (3×50 mL). The combined organic extracts were washed successively with 1M HCl (50 mL), water (50 mL) and brine (20 mL), then dried over MgSO4 and concentrated. The resulting residue was purified by chromatography (EA/hexane) to provide 2.3 g (72%) of (S)-methyl 3-(4-(tert-butyl)benzamido)-4-(4-hydroxyphenyl)butanoate as white needles. LCMS-ESI (m/z) calculated for C22H27NO: 369.4. found 370.0 [M+H]+, tR=2.52 min (Method 6).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:12][CH2:13][CH:14]=[CH2:15].[BH4-].[Na+]>>[CH2:15]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH2:14][CH:13]=[CH2:12]
Reactant: c1cnc2ccncc2c1
Reactant: C=CCCBr
Agent: [BH4-]
Agent: [Na+]
Product: C=CCCN1CCc2ncccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,6-naphthyridine (3.9 g, 0.03 mol) and 4-bromo-1-butene (4.9 g, 0.036 mol) was heated at 70°-80° C. for 5 hours. The reaction mixture was washed with a small quantity of ether, dissolved in methanol (200 ml) and water (60 ml). To the mixture, sodium borohydride (5.7 g, 0.15 mol) was added portionwise over the internal temperature range 0° to 20° C. After stirring overnight at room temperature, the mixture was evaporated in vacuo, water added and extracted with benzene. The benzene layer was dried over anhydrous potassium carbonate and evaporated in vacuo. The resulting residue was purified by alumina column chromatography (eluted successively with petroleum ether, benzene and chloroform) and distilled, bp. 100°-103° C./0.9 mmHg, to afford the Compound No. 14 (1.6 g, 28.4%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[NH:15][N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[C:31]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]([CH3:31])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc3c(-c4ccccc4)n[nH]c3c(=O)n2-c2ccc(Br)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cc1ccc(-c2nc3c(-c4ccccc4)nn(C)c3c(=O)n2-c2ccc(Br)cc2)cc1

Procedure:
To a solution of 6-(4-bromo-phenyl)-3-phenyl-5-p-tolyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (11.0 mg, 0.024 mmol) in acetonitrile (0.3 mL) are added K2CO3 (6.6 mg, 0.048 mmol) and MeI (5.99 μL, 0.096 mmol). The reaction mixture is stirred at room temperature for overnight before the removal of K2CO3 by filtration. The filtrate is concentrated and purified by preparative LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.36 (d, 2H), 7.47 (t, 2H), 7.44 (d, 2H), 7.35 (t, 1H), 7.22 (d, 2H), 7.04 (m, 4H), 4.37 (s, 3H), 2.31 (s, 3H); HPLC-MS calculated for C25H19BrN4O (M+H+) 471.1. found: 471.1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:3]=1.[OH-:17].[Na+].Cl.[CH3:20]O>>[CH3:20][O:17][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:3]=1
Reactant: [OH-]
Reactant: CNc1cnc(Cl)cc1-c1ccccc1C
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: CNc1cnc(OC)cc1-c1ccccc1C

Procedure:
6-Chloro-N-methyl-4-o-tolylpyridin-3-amine (150 mg, 0.645 mmol, prepared as described in WO2005/002577) in a 10% NaOH solution in CH3OH (300 mg NaOH in 3 mL CH3OH) was heated to 160° C. for 3 hours. After cooling, the reaction mixture was neutralized with 6M aqueous HCl and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles in vacuo gave a gummy oil. The desired compound was isolated by flash chromatography on silica gel (20% EtOAc in n-hexane) as a white waxy solid (115 mg, 78%).
Reaction SMILES: [NH3:1].C([O:4][C:5]([CH:7]([NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1)[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)=O)C>C(O)C>[C:5]([CH:7]([NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1)[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)(=[O:4])[NH2:1]
Reactant: CCOC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Reactant: N
Solvent: CCO
Product: NC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
20 ml of a 10 % solution of ammonia in ethanol was added to 200 mg of 4-(α-ethoxycarbonyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was stirred at room temperature for 3 days. The crystal thus precipitated was recovered by filtration. Thus, 60 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][OH:16])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].CCN(C(C)C)C(C)C.Cl[CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][CH2:15][O:16][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COCCOCCl
Reactant: COC(=O)c1cccc2c1ccn2CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOCCn1ccc2c(C(=O)OC)cccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of -(2-Hydroxy-ethyl)-1H-indole-4-carboxylic acid methyl ester in DCM (3 ml) is added DIPEA (0.129 ml, 0.739 mmol) and 1-Chloromethoxy-2-methoxy-ethane (0.084 ml, 0.739 mmol). The solution is stirred at room temperature for 72 hours. The reaction is diluted with DCM (50 ml) and washed with 0.5 M HCl (20 ml), 1 M NaOH (20 ml) and 0.5 M HCl (20 ml). The organic layer is dried over MgSO4 and the solvent is removed in vacuo. Purification by chromatography (SiO2, DCM/MeOH) affords 1-[2-(2-Methoxy-ethoxymethoxy)-ethyl]-1H-indole-4-carboxylic acid methyl ester; [M+H]+ 308
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:25][CH3:26])[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](B2OC(C)(C)C(C)(C)O2)[C:14]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][N:34]=[C:33](Br)[CH:32]=1.N#N>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:28][O:29][C:30]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:13]2[CH:12]=[N:11][CH:10]=[C:9]([CH2:8][N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:27])[CH2:25][CH3:26])[C:14]=2[CH3:15])[CH:32]=1)=[O:38]
Reactant: CCN(Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1C)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccnc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: C1COCCO1
Solvent: O
Product: CCN(Cc1cncc(-c2cc(C(=O)OC)ccn2)c1C)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 69.2 %

Procedure:
Ethyl-[4-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester (1.5 g, 5.1 mmol) and 2-bromo-isonicotinic acid methyl ester (1.3 g, 6.1 mmol) were suspended in 1,4-dioxane (25 mL). To the mixture was added K3PO4.3H2O (0.90 g, 4.52 mmol, 1 M in water). The reaction was degassed with N2 and PdCl2(PPh3)2 (72 mg, 0.1 mmol) was added. The reaction was heated to 60° C. for 3 hours. The mixture was then diluted with water and neutralised to pH 7. The mixture was concentrated in vacuo, to remove organic solvent, and then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with water, brine, dried (MgSO4) and then evaporated to dryness. Purification by SiO2 chromatography gave the title compound (1.36 g). m/z 386 (M+H)+
Reaction SMILES: [P:1]([O-])([O:5]CC)[O:2][CH2:3][CH3:4].O.[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH3:11]>C(O)C>[CH2:3]([O:2][P:1]=[O:5])[CH3:4].[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][NH3+:16])[CH3:11]
Reactant: CCOP([O-])OCC
Reactant: CCOCCCN
Solvent: CCO
Solvent: O
Product: CCOCCC[NH3+]
Product: CCOP=O
Yield: 99.9 %

Procedure:
A mixture of 13.81 g. (0.1 moles) of diethyl phosphite, 20 ml. of water and 20 ml. of ethanol is reacted with a mixture of 10.31 g. (0.1 moles) of 3-ethoxypropyl amine and 30 ml. of ethanol as described in Example 1. 21.3 g. (99.9%) of 3-ethoxypropyl-ammoniumethyl phosphanate are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:35])[C:20]4[C:21]([O:27][C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:22](Cl)[N:23]=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH:41]=[N:40][CH:39]=[N:38]1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:35])[C:20]4[C:21]([O:27][C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:22]([N:40]3[CH:39]=[N:38][N:37]=[CH:41]3)[N:23]=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-n5cnnc5)nccc4c3=O)cc2)CCC1
Temperature: 150 °C
Yield: 185.3 %

Procedure:
To a microwave vial were added {1-[4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (6.7 mg, 0.0133 mmol), 1,2,4-triazole (4.6 mg, 0.067 mmol), cesium carbonate (8.7 mg, 0.0266 mmol), copper(I) iodide (0.8 mg, 0.004 mmol) and NMP (0.5 mL). The reaction mixture was heated in a microwave reactor at 150° C. for 30 minutes. The reaction was repeated with {1-[4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (20 mg, 0.04 mmol), 1,2,4-triazole (13.8 mg, 0.2 mmol), cesium carbonate (26.1 mg, 0.08 mmol), copper(I) iodide (2.4 mg, 0.012 mmol) and NMP (0.7 mL). The reaction mixtures were combined and partitioned between EtOAc and water. The organic phase was extracted further with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 75% EtOAc in cyclohexane) to afford the title compound (13.2 mg, 46%) as a colourless gum. LCMS (Method H): RT=3.84 min, [M+H]+=536.
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[C:14](=[S:17])([NH2:16])[CH3:15]>CN(C)C=O>[CH3:15][C:14]1[S:17][C:2]2[CH2:3][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=2[N:16]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2nc(C)sc2C1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 387A (4.4 g) and ethanethioamide (1.33 g) in N,N-dimethylformamide (50 mL) was heated at 140° C. for 20 hours. After it cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH3:33][S:34]([O:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:6]=[CH:5][CH:4]=1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc(CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc(COS(C)(=O)=O)n1
Reaction time: 2 h
Yield: 104.2 %

Procedure:
tert-Butyl (2S)-2-({[6-(hydroxymethyl)pyridin-2-yl]oxy}methyl)piperidine-1-carboxylate (520 mg, 1.61 mmol) and DIPEA (0.842 ml, 4.84 mmol) dissolved in DCM (10 ml) was cooled using an ice bath. Methanesulfonyl chloride (0.191 ml, 2.419 mmol) was added and the reaction stirred for 2 h. DCM (150 ml) and water (150 ml) were added and the phases separated. The organic phase washed with water (150 ml), dried through a phase separator and evaporated in vacuo, yielding the title compound as a light yellow oil (672 mg (104%)) which was used directly in the next step without further purification. MS (ESI+) 401.20 (M+1H+)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=O)([O-:3])=[O:2].Cl.CN.C1C=CC2N(O)N=[N:25][C:23]=2C=1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC>CN1CCCC1=O.C(OCC)(=O)C>[CH3:23][NH:25][C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1)=[O:15]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of compound 54 (100 mg, 0.483 mmol), methylamine hydrochloride (52.2 mg, 0.773 mmol), HOBt (130 mg, 0.966 mmol) and DIEA (0.34 mL, 1.95 mmol) in N-methylpyrrolidinone was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148 mg, 0.773 mmol). The reaction was stirred at room temperature for 2 hrs and diluted with 10 mL of ethyl acetate. The mixture was washed with water and a yellow solid precipitated. The precipitate was collected by filtration to give compound 55 (67 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[NH:6][N:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[CH3:1][O:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[NH:6][N:5]=1
Reactant: CCOC(=O)c1cc(COC)n[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1cc(C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Ethyl 3-(methoxymethyl)-1H-pyrazole-5-carboxylate (2.44 g, 13.25 mmol) dissolved in methanol (40 ml) and cesium carbonate (8.63 g, 26.5 mmol) dissolved in water (40 ml) were loaded into a flask and stirred overnight at RT under nitrogen atmosphere. Ethyl acetate (100 ml) and water (100 ml) were added and the pH was adjusted to 3 with 10% citric acid. Phases were separated and the water phase was extracted with more ethyl acetate. The combined organic phases were dried with Na2SO4, filtered and evaporated. The product was purified with flash chromatography. Yield 36.5%. 1H-NMR (400 MHz; DMSO-d6): δ 3.25 (s, 3H), 4.40 (s, 2H), 6.67 (s, 1H), 13.16 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCO
Reactant: Fc1ncnc(F)c1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.62 ml of triethylamine were added to 1 ml of toluene, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.56 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.CCN(CC)CC.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>ClCCl>[C:30]([N:13]1[CH2:14][CH2:15][C@@H:11]([NH:10][C:9]2[N:8]=[CH:7][C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][C:4]=2[Cl:3])[CH2:12]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)c3ccccc3)C2)c(Cl)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To an ice-cooled solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridyl}acrylate dihydrochloride (330 mg) and Et3N (0.437 ml) in dichloromethane (8 ml) was added benzoyl chloride (132 mg), the mixture was stirred at 23° C. for 1 hour. The mixed solution was poured into a mixture of water (20 ml) and DCM (15 ml). The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (12 g) using a mixed solvent of dichloromethane and MeOH (100:1 to 40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. ethyl (2E)-3-(6-{[(3R)-1-benzoyl-3-pyrrolidinyl]amino}-5-chloro-3-pyridyl)acrylate (245 mg) was obtained as colorless syrup.
Reaction SMILES: [Cl:1][CH:2]=[CH:3]Cl.N1CCCCC1.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)#[CH:12]>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.[Cu]I.C1COCC1>[Cl:1]/[CH:2]=[CH:3]/[C:12]#[C:11][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: ClC=CCl
Reactant: C#Cc1ccc(C=O)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: O=Cc1ccc(C#C/C=C/Cl)cc1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 59 %

Procedure:
1,2-Dichloroethylene (3.0 mL), tetrakis(triphenylphosphine)palladium (0.44 g), CuI (73 mg) and piperidine (1.1 mL) were added to a THF (20 mL) solution of 4-ethynylbenzaldehyde (1.0 g), and the mixture was stirred for 22.5 hours at room temperature in a nitrogen atmosphere. IPE was added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (hexane/ethyl acetate/chloroform=9/1/1) to obtain 4-((E)-4-chlorobut-3-en-1-yn-1-yl)benzaldehyde (light brown solid) (0.87 g, 59%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[C:16]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:16][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)n(-c2cc(C#N)ccn2)n1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)nn1-c1cc(C#N)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
To a solution of 2-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (200 mg, 1 mmol) and K2CO3 (276 mg, 2 mmol) in DMF was added MeI (213 mg, 1.5 mmol) dropwise at −20° C. The mixture was warmed to 0° C. and stirred for 3 h. Water was added, and the reaction mixture was extracted with EtOAc, then washed with water and brine. The organic phase was dried, concentrated, and purified by prep-HPLC to afford the title compound (50 mg). [M+H] Calc'd for C11H10N4O, 215; Found, 215.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:10][NH:9]/[C:8](=[N:11]\[C:12]([C:14]2[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=2)=[O:13])/[NH:7]1.C(N(CC)CC)C.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:30]1([CH2:36][C:37]([CH:2]([NH2:1])[CH2:3][CH2:4][CH2:5][C@H:6]2[CH2:10][NH:9]/[C:8](=[N:11]\[C:12]([C:14]3[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=3)=[O:13])/[NH:7]2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCCC[C@H]1CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCC(N)C(=O)Cc3ccccc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [(S)-4-(4-amino-butyl)-imidazolidin-(2E)-ylidene]-amide (Intermediate T) (0.032 g, 0.098 mmol) in DMF (1 ml) is added triethylamine (0.014 ml, 0.098 mmol) followed by phenylacetyl chloride (0.013 ml, 0.098 mmol). The suspension is stirred at room temperature for 90 minutes before a further 0.5 equivalents of phenylacetyl chloride (0.006 ml, 0.049 mmol) is added. The reaction is left to stir at room temperature for a further 18 hours. Purification by reverse phase chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA) followed by catch and release resin (SCX-2) eluting with MeOH and 7M NH3 in MeOH affords the title compound as an off-white solid; [M+H]+ 445.1
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:33]=[C:32]3[C:28]([CH2:29][C:30](=[O:34])[NH:31]3)=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:29]1[C:28]2[C:32](=[CH:33][C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[CH:26][CH:27]=2)[NH:31][C:30]1=[O:34])([CH3:3])[CH3:2]
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2cc(C(C)C)c(OC)c(C(C)C)c2)c1

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-(3-methoxyphenyl)-2-oxindole to give 0.4 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-6-(3-methoxyphenyl)-1,3-dihydroindol-2-one as a yellow-orange solid.