Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:29])[C:3]([NH:5][CH:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([O:9]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])=[O:4].Cl>C(O)(=O)C>[NH2:1][C:2](=[O:29])[C:3]([NH:5][CH:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: NC(=O)C(=O)NC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)C(=O)NC(C(=O)O)c1ccccc1
Reaction time: 0.25 h

Procedure:
13 g. of the product of Example 12 are added to 250 ml. of a 6N solution of hydrochloric acid in glacial acetic acid. After stirring for 15 minutes everything dissolves. The reaction solution is evaporated at room temperature and the white crystalline residue is triturated with ether, filtered under suction and recrystallized from water to obtain DL-α-[(2-amino-1,2-dioxoethyl)amino]phenylacetic acid as white crystals, m.p. 193°.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Mg]Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[OH:8][C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)c2ccccc2)C1
Solvent: C1CCOC1
Product: CCCCCCC(O)(c1ccccc1)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -10 °C
Reaction time: 17 h

Procedure:
To a 100-mL round bottom flask were added tert-butyl 3-(benzoyl)piperidine-1-carboxylate (0.4733 g, 1.63 mmol, 1.0 equiv) and THF (5 mL). The flask was evacuated and refilled with N2. The mixture was cooled with a dry ice-acetone bath and hexylmagnesium bromide (2.0M solution in Et2O, 2.5 mL, 5.0 mmol, 3.0 equiv) was added. The reaction mixture was allowed to slowly warm to −10° C. while stirring overnight (17 h). The mixture was quenched with saturated NH4Cl (10 mL), extracted three times with EtOAc, and dried over Na2SO4. The crude product was purified by reversed-phase HPLC (XTerra® Prep MS C18 OBD™ Column, 5 μm, 19×50 mm, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min, flow rate 20 mL/min) to give tert-butyl 3-(1-hydroxy-1-phenylheptyl)piperidine-1-carboxylate. LC-MS (3 min) tR=2.41 min, m/z 398 (M+Na+), 376 (MH+), 302, 276, 258.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:18].[OH-].[Na+].CO>C(Cl)Cl>[OH:18][C:7]1[CH:6]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cccc(OCCF)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Oc1cccc(OCCF)c1
Yield: 76.2 %

Procedure:
In a manner similar to that described by Godfrey et al., (J. Chem. Soc. Perkin I, 1353-1354 (1974), the reaction of 7.0 grams (0.042 mole) of 3-(2-fluoroethoxy)benzaldehyde with 3-chloroperoxybenzoic acid (14.0 grams of 75% technical, 0.061 mole) in 100 ml of dry methylene chloride followed by treatment with an aqueous, 15% sodium hydroxide solution and methanol yielded 5.0 grams of 2-fluoroethyl 3-hydroxyphenyl ether as an oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.11 mmol), 4-aminobutyric acid (3.76 g, 36.5 mmol) and NaOMe solution (54 mL, 27.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1M HCl was added with vigorous stirring until pH was about 1. The organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 35 mg of the title compound. MS: (+) m/z 483.16 (M+1).
Reaction SMILES: C(N)(=O)C.FC(F)(F)[C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[O:10]CC(O)=O.[CH3:20][N:21]([CH3:36])[C:22](=O)[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.B.O1CCCC1>>[CH3:20][N:21]([CH3:36])[CH2:22][CH:23]([C:9]1([OH:10])[CH2:15][CH2:16][CH2:17][CH2:7][CH2:8]1)[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1
Reactant: CN(C)C(=O)COc1cccc(C(F)(F)F)c1
Reactant: O=C(O)COc1cccc(C(F)(F)F)c1
Agent: B
Agent: CC(N)=O
Solvent: C1CCOC1
Product: CN(C)CC(Oc1cccc(C(F)(F)F)c1)C1(O)CCCCC1

Procedure:
N,N-dimethyl-2-[3-trifluoromethyl)phenoxy]acetamide, prepared from 2-[3-trifluoromethylphenoxyl]acetic acid in accordance with Example 1 was converted to the amide which was reduced with Borane/tetrahydrofuran as in Example 3. The title compound was obtained and its hydrochloride salt prepared, m.p. 210°-211° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29]([O:31]CC)=[O:30])[CH:9]=2)[C:5]([C:34]#[C:35][Si](C)(C)C)=[CH:4][N:3]=1.[OH-].[K+].CCO>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29]([OH:31])=[O:30])[CH:9]=2)[C:5]([C:34]#[CH:35])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(-c2nc(N)ncc2C#C[Si](C)(C)C)n(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C#Cc1cnc(N)nc1-c1cc(C(=O)O)c(-c2cc(Cl)ccc2C)n1COCC[Si](C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Ethyl 5-{2-amino-5-[(trimethylsilyl)ethynyl]pyrimidin-4-yl}-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate (466 mg, 0.8 mmol) was treated with a 1.5 M solution of potassium hydroxide in 95% EtOH (5.33 mL, 8 mmol) and stirred at 50° C. overnight. After cooling, the residue was concentrated, dissolved in water and washed with DCM. The aqueous layer was acidified until pH<1 with the addition of 2 N HCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and the solvent evaporated under vacuum to obtain the title compound as an orange oil (367 mg, 95%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1.[CH3:23][NH:24][CH3:25].CC(O)=O>ClCCCl>[Br:15][C:16]1[O:20][C:19]([CH2:21][N:24]([CH3:25])[CH3:23])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)Cc1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Sodium triacetoxyborohydride (844 mg, 4 mmol) was added to a solution of 5-bromo-furan-2-carbaldehyde (350 mg, 2 mmol) and dimethyl amine (2 ml, 2M solution in THF) in 10 ml of 1,2-dichloroethane (DCE). 0.2 ml of HOAc was then added. The mixture was stirred at room temperature overnight, followed by addition of 15 ml of DCE. The organic phase was washed with water, dried over sodium sulfate. The solvent was removed by rotovap to give 400 mg of (5-bromo-furan-2-ylmethyl)-dimethyl-amine, yield: 97%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.[C:40]([N:47]1[CH2:52][CH2:51][CH:50](O)[CH2:49][CH2:48]1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>O1CCCC1.O>[C:43]([O:42][C:40]([N:47]1[CH2:52][CH2:51][CH:50]([O:39][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)[CH2:49][CH2:48]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2)CC1
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
To a solution of triphenyl phosphine (7.7 g, 29 mmol), in tetrahydrofuran (40 mL), diethylazodicarboxylate (5.12 g, 29 mmol) was added and the solution was stirred for 20 minutes. 4-Fluorophenol (3 g, 27 mmol) was added and the mixture was stirred for another 20 minutes at 0° C. N—Boc-4-hydroxypiperidine (5.9 g, 29 mmol) was added dissolved in tetrahydrofuran (20 mL) and the mixture was stirred at room temperature overnight. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with hexane:ethyl acetate (1:0 to 1:1) to give 4.8 g (60%) of the product as a white solid. MS (m/e): 296.3 (M−H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[CH:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[CH2:15])[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1)[NH2:24].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:11]1([CH2:10][O:9][CH2:8][C:6]2[CH:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[CH2:15])[N:3]=[C:2]([NH:24][C:23]3[CH:25]=[CH:26][C:27]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:21]([O:20][CH3:19])[CH:22]=3)[N:7]=2)[CH2:13][CH2:12]1
Reactant: C=C(OCC)c1cc(COCC2CC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(COCC2CC2)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 120 °C
Yield: 68.2 %

Procedure:
A mixture of 2-chloro-4-((cyclopropylmethoxy)methyl)-6-(1-ethoxyvinyl)pyrimidine (88 mg, 0.33 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (67 mg, 0.33 mmol), cesium carbonate (213 mg, 0.65 mmol), palladium acetate (11 mg, 0.05 mmol) and 2-(dicyclohexylphosphino)biphenyl (17 mg, 0.05 mmol) in dioxane (2 mL) were heated under argon atmosphere at 120° C. for 90 minutes in microwave reactor. The mixture was filtered through a short silica plug which was washed with 10% MeOH in EtOAc. The solvents were evaporated and the residue was purified by preparative to give the title compound 98 mg (69%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][OH:10])([CH3:8])[CH2:3]1.[H-].[Na+].F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][O:10][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])([CH3:8])[CH2:3]1
Reactant: CN1CCCC(C)(CO)C1
Reactant: N#Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC(C)(COc2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (1,3-dimethylpiperidin-3-yl)methanol (0.50 g, 3.5 mmol) in dry DMF (10 mL) at room temperature, 60% sodium hydride in oil (0.28 g, 7.0 mmol) was added. The reaction mixture was stirred at room temperature for 5 minutes and 3-fluoro benzonitrile (0.44 g, 3.7 mmol) was added. Due to excessive foaming the reaction mixture was diluted with dry DMF to 15 mL. The reaction mixture was then stirred at room temperature over night and quenched with water. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient with EtOAc:MeOH:TEA (1:0.1:0.05) in EtOAc, which gave the product as a colorless oil. Yield: 0.53 g (59%). 1H NMR (400 MHz, CD3OD) δ 7.41 (t, 1H, J=8.11 Hz), 7.20-7.27 (m, 3H), 3.89 (d, 1H, J=8.89 Hz), 3.82 (d, 1H, J=8.89 Hz), 2.21-2.51 (m, 3H), 2.19 (s, 3H), 2.12 (m, 1H), 1.54-1.67 (m, 3H), 1.21-1.30 (m, 1H), 1.07 (s, 3H).
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35]>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:35][CH2:34][CH2:33][C:32]([O:31][CH3:30])=[O:36])=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Reactant: COC(=O)CCN
Agent: Cl
Product: COC(=O)CCNCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24) and beta-alanine methyl ester hydrochloride (Fluka), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]#[N:19]>>[CH3:12][N:13]1[C:17]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)=[CH:16][CH:15]=[C:14]1[C:18]#[N:19]
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: Cn1cccc1C#N
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)CCC2=O

Procedure:
The title compound was prepared from 5-bromo-1-indanone and 1-methyl-2-cyanopyrrole according to the coupling procedure as described in example 1. MS (ESI) m/z 237; HRMS: calcd for C15H12N2O+H+, 237.1022; found (ESI, [M+H]+), 237.1003; Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found: C, 75.99; H, 4.92; N, 11.80.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>O1CCOCC1.CO.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>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:18][CH:17]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cnc(-c2ccc(Cl)cc2)cn1
Temperature: 110 °C

Procedure:
50 mL of 2N sodium carbonate solution and 1.16 g (1.00 mmol) of Pd(PPh3)4 were added to a solution of 8.70 g (174 mmol) of 5-bromopyrazin-2-ylamine and 7.98 g (156 mmol) of 4-chlorophenylboric acid in 150 mL of 1,4-dioxane and 50 mL of MeOH and the mixture was heated to 110° C. for 2.5 hours. The reaction mixture was evaporated down in vacuo and diluted with EtOAc. The organic phase was washed with water, dried over sodium sulfate, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, DCM→DCM/MeOH 20:1). Yield: 8.30 g (81% of theoretical); C10H8ClN3 (M=205.643); calc.: molpeak (M+H)+:206/208 (Cl); found: molpeak (M+H)+:206/208 (Cl); HPLC-MS: 7.15 minutes (method G).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(OCC3CC3)c2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (300 mg, 1.36 mmol, 1 eq) under nitrogen was added potassium carbonate (377 mg, 2.73 mmol, 2 eq), 5 mL of DMF and bromomethylcyclopropane (145 uL, 1.50 mmol, 1.1 eq) and the reaction was stirred at room temperature for 16 h. After work-up and flash column chromatography, 4-cyclopropylmethoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 94% yield (350 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.4 (m, 2 H) 0.6 (m, 2 H) 1.3 (m, 1 H) 1.3 (d, J=14.4 Hz, 3 H) 2.7 (d, 3 H) 4.0 (d, J=6.8 Hz, 2 H) 4.3 (q, J=7.1 Hz, 2 H) 6.8 (dd, J=8.1, 0.5 Hz, 1 H) 7.2 (dd, J=8.3, 0.5 Hz, 1 H) 7.4 (t, J=8.2 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[C:3]([NH2:10])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(OCC)(=O)C>[NH2:10][C:3]1[C:2](/[CH:13]=[CH:12]/[C:11]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[N:4]=1
Reactant: C=CC(=O)OCC
Reactant: COc1ncc(Cl)c(N)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc(OC)nc1N
Temperature: 122.5 °C
Reaction time: 5 h

Procedure:
To 2.9 g of 5-chloro-2-methoxypyrimidin-4-amine, 2.35 mL of ethyl acrylate, 18 mL of triethylamine, and 0.46 g of bis(tri-tert-butylphosphine)palladium(0) were added, and the mixture was stirred at an external temperature of 115 to 130° C. for 5 hours in a sealed tube. Thereto were further added 5 mL of triethylamine, 0.30 g of bis(tri-tert-butylphosphine)palladium(0) and 0.5 mL of ethyl acrylate, and the mixture was stirred at an external temperature of 120 to 130° C. for 6 hours 30 minutes in a sealed tube. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with chloroform and ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 0.89 g of ethyl (2E)-3-(4-amino-2-methoxypyrimidin-5-yl)acrylate as a yellow solid.
Reaction SMILES: [Br:1][C:2](Br)([P:19](=[O:34])([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[P:3](=[O:18])([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)C.Cl[Sn]Cl>O>[Br:1][CH:2]([P:3](=[O:18])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[P:19](=[O:34])([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCOP(=O)(OCCCCCC)C(Br)(Br)P(=O)(OCCCCCC)OCCCCCC
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCCCCCOP(=O)(OCCCCCC)C(Br)P(=O)(OCCCCCC)OCCCCCC
Temperature: 0 °C

Procedure:
Into a solution containing 6.7 g (0.01 moles) of tetrahexyl (dibromomethylene)bisphosphonate in 70 ml of abs. ethanol, 2.5 g of SnCl2 ×2H2O in 100 ml of water are added while stirring at 0° C. After the addition, the mixture is stirred for 15 minutes and extracted with chloroform and the extract is dried (MgSO4) and filtered. The filtrate is evaporated under a vacuum, whereby about 4.1 g (70% of the theor.) of tetrahexyl (monobromomethylene)bisphosponate (31P-NMR (CDCl3): δ 13.83 ppm) are obtained as a colourless oil, at a concentration of 90%.
Reaction SMILES: [CH3:1]C(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-].[C:13]([SiH2:17][O:18][C:19]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:20]([NH:24][C:25](=[O:42])[CH:26]([O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][C:34]([C:40]#[CH:41])=[CH:33]2)[S:27][CH3:28])([CH3:23])[CH:21]=O)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.[Cl-].[Na+].O>[C:13]([SiH2:17][O:18][C:19]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:20]([NH:24][C:25](=[O:42])[CH:26]([O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][C:34]([C:40]#[CH:41])=[CH:33]2)[S:27][CH3:28])([CH3:23])[C:21]#[CH:1])([CH3:14])([CH3:15])[CH3:16]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C=O)C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc2c1
Reactant: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#C)C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc2c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of dimethyl-1-diazo-2-oxopropylphosphonate (0.86 g) in dry methanol (20 ml) was added at R.T. to a solution of crude N-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-1-methyl-2-oxo-ethyl]-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide in dry methanol (40 ml). The reaction medium was cooled down to 0° C. and Potassium carbonate (0.773 g) was added portion wise along with additional dry methanol (10 ml). The reaction mixture was allowed to warm up to R.T., further stirred for 16 hrs and then poured onto a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted thrice with ethyl acetate. The organic layers were combined, washed once with brine and then dried over sodium sulphate. After filtration and concentration under reduced pressure 1.84 g of crude mixture were isolated as a dark orange oil. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate) to give 1.523 g of N-[1-(tert-butyl-diphenyl-silanyloxymethyl)-1-methyl-prop-2-ynyl]-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)ccc1Nc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
To a room temperature solution of 4-bromo-1-fluoro-2-nitrobenzene (3.3 g, 15 mmol) and 4-fluorophenylamine (1.42 mL, 15 mmol) in anhydrous acetonitrile (20 mL) was added N,N-diisopropylethylamine (2.9 mL, 16.5 mmol) and the mixture was warmed to 90° C. After 24 hours, the mixture was concentrated in vacuo and the crude material was purified by column chromatography over silica gel eluting with 0-20% ethyl acetate in hexanes to afford 4.7 g of (4-bromo-2-nitrophenyl)-(4-fluorophenyl)amine as an orange oil which solidified on standing. MS m/z 311/313 (MH+).