Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.C([Li])CCC.CN(C)[C:18](=[O:20])[CH3:19].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][C:18](=[O:20])[CH3:19])[CH:4]=1
Reactant: Cc1cc(N(C)C)ccn1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)Cc1cc(N(C)C)ccn1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-dimethylamino-2-methylpyridine (1.30 g) in tetrahydrofuran (13 ml) was added a solution of n-butyllithium in n-hexane (1.56M, 7.34 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.15 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with brine, dried over sodium sulfate and-evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 20% methanol in dichloromethane) to give 1-(4-dimethylaminopyridin-2-yl)propan-2-one (1.29 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([O:17][CH3:18])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[OH-].[K+]>C1COCC1.CCOCC>[CH3:18][O:17][C:8]1[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(OC)c(-c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(-c2ccccc2)cc(C(=O)O)cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
At ambient temperature, to a stirred solution of 2'-methoxy-[1,1';3',1"]terphenyl-5'-carboxylic acid methyl ester (1.148 g, 3.606 mmol) in THF (36.06 mL) was added 1N KOH (36.06 mL) and the reaction was stirred for 16 h. The reaction was heated at 100° C. for an additional 24 h. The reaction was cooled to ambient temperature, diluted with ether (100 mL) and extracted with 0.1N NaOH. The aqueous extracts were washed with ether (3×), acidified with 6N HCl and extracted with EtOAc. The organic extracts were dried (MgSO4) and concentrated to give 1.043 g (95%) of the title compound. 1H NMR (DMSO-d6) δ 3.15 (s, 3 H), 7.40-7.52 (m, 6 H), 7.58-7.60 (m, 4 H), 7.88 (s, 2 H), 13.04 (s, 1 H).
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][OH:7].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>ClCCl.C(=O)([O-])O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][O:7][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: CSC(=S)NCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CSC(=S)NCCOC1CCCCO1
Reaction time: 1 h
Yield: 101.5 %

Procedure:
To a solution of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (81.7 g) in dichloromethane (300 ml) are added dihydropyran (54 g) and toluene-p-sulfonic acid monohydrate (1.0 g), and the mixture is stirred for 1 hour. The reaction mixture is poured in aqueous sodium hydrogen carbonate, shaken and the resulting organic layer is separated. The layer is concentrated under reduced pressure to give N-[2-(2-tetrahydropyranyl)oxyethyl]dithiocarbamic acid methyl ester (129 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10])(=[O:34])=[O:33]
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 2-methoxy-4-nitrobenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight or until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with 10% aqueous HCl (20 mL), water (20 mL), and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to yield 353 mg of benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-4-nitrobenzenesulfonylamino)phenyl]-amide. LC: Tr 1.21 min; MS: 520.7.7 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.24 (s, 3H), 6.72 (bs, 1H), 6.88 (d, 1H), 7.03 (t, 1H), 7.16 (t, 1H), 7.30 (d, 1H), 7.52 (t, 1H), 7.51 (t, 1H), 7.64 (s, 1H), 7.67-7.88 (m, 5H), 7.92 (s, 1H) ppm.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][C:7]([S:10]([CH2:13]P(OCC)(=O)OCC)(=[O:12])=[O:11])=[N:8][CH:9]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1C=CC=CC=1>[CH:13](/[S:10]([C:7]1[N:8]=[CH:9][C:4]([Cl:3])=[CH:5][N:6]=1)(=[O:11])=[O:12])=[CH:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(CS(=O)(=O)c1ncc(Cl)cn1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=S(=O)(/C=C/c1ccccc1)c1ncc(Cl)cn1

Procedure:
Sodium hydride dispersion (55-60%, 2 mmol) was further dispersed in benzene (4 ml) and added gradually to a solution of diethyl (5-chloropyrimidin-2-sulfonyl)methanephosphonate (0.66 g, 2 mmol) in benzene (4 ml). The mixture was stirred for 10 min before a solution of benzaldehyde (0.21 g, 2 mmol) in benzene (2 ml) was added. The resultant mixture was stirred at room temperature overnight before extraction with water. Evaporation of the dried (MgSO4) benzene solution left the product which was recrystallised from ethanol; yield 0.20 g 35%, m.p. 150° C. 1H NMR (CDCl3): δ7.24 and 7.90 (2H-vinyl, Jvic 16 Hz), 7.60 (Ph, m.), 8.90 (2H-4,6).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[NH:4][CH2:3]1>C(OCC)(=O)C.[Pd]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:14])([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CNc2cc(N)ccc21
Yield: 89.5 %

Procedure:
A solution of 3,3-dimethyl-6-nitroindoline (60 mg, 0.31 mmol) in 3 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (10 mg) at rt for 3 h. Filtration over celite afforded 45 mg (90%) of 6-amino-3,3-dimethylindoline. Data for 6-amino-3,3-dimethylindoline: 1H NMR (400 MHz, CDCl3)6.80 (d, J=7.8, 1H), 6.08 (dd, J=7.8, 2.1, 1H), 6.01 (d, J=2.1, 1H), 3.60 (bs, 1H), 3.50 (bs, 2H), 3.26 (s, 2H), 1.25 (s, 6H).
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: CCN(C(=O)C1CC1C(=O)Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCNCc1ccccc1
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: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:46][C:45]5[CH:44]=[CH:43][C:42]([CH2:41][N:38]6[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]6)=[CH:48][CH:47]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(Cc2ccc(N)cc2)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: CN(C)C=O
Product: COc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)cc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
In a dry round bottom flask, 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (89.4 mg, 0.2 mmol), 4-((4-methylpiperazin-1-yl)methyl)aniline hydrochloride (66.7 mg, 0.24 mmol) were dissolved in dry N,N-dimethylformamide (3.0 mL). Then added diisopropylethylamine (107 μL, 0.6 mmol) and finally HATU (114 mg, 0.3 mmol) to the reaction, continued at room temperature for 2 hours. After completion, purified the product using reverse phase HPLC using water-acetonitrile solvent system. Pure fractions were mixed and evaporated to a minimal amount then basified with sat.NaHCO3 solution and extracted into EtOAc ((2×100 mL), combined organic layer was washed with sat. brine solution, dried over Na2SO4 and evaporated to get the pure product 72 mg (57% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.80 (m, 6 H) 1.97 (br. s., 2 H) 2.15 (s, 3 H) 2.34 (br. s., 8 H) 3.42 (s, 2 H) 3.93 (s, 3 H) 4.07 (t, J=12 Hz, 2 H) 4.80 (t, J=8.21 Hz, 1 H) 7.26 (d, J=8.59 Hz, 2 H) 7.51-7.67 (m, 2 H) 7.70 (m, J=8.59 Hz, 2 H) 8.05 (s, 1 H) 8.29 (s, 1 H) 8.37 (d, J=8.34 Hz, 1 H) 10.09 (s, 1 H). [M+H] calc'd for C33H40F2N8O3, 635; found 635.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl[CH2:14][CH:15]([O:18][CH2:19][O:20][CH3:21])[CH2:16]Cl>CS(C)=O.C(OCC)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:16][CH:15]([O:18][CH2:19][O:20][CH3:21])[CH2:14]2)=[CH:6][CH:5]=1
Reactant: COCOC(CCl)CCl
Reactant: N#CCc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COCOC1CC(C#N)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
Potassium hydroxide (2.57 g) was dissolved in dimethyl sulfoxide (8.0 mL). (4-Chlorophenyl)acetonitrile (1.58 g, 10.4 mmol) and 1,3-dichloro-2-(methoxymethoxy)propane (1.993 g) were dissolved in ethyl ether (3 mL), and this mixture was added dropwise to the vigorously stirred potassium hydroxide solution at room temperature. After stirring at room temperature for one hour, the reaction was quenched by adding ice-cold water (5.5 mL). The mixture was filtered through a pad of celite which was washed with ether (30 mL). The filtrate was added to a separatory funnel, and the aqueous layer was extracted with ether (3×15 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The product was purified by silica gel chromatography to provide 1-(4-chlorophenyl)-3-(methoxymethoxy)cyclobutanecarbonitrile (1.28 g) as a mixture of isomers (ca. 2:1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>>[CH3:14][N:15]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=1)[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1ccc(C(F)(F)F)cc1
Product: CN(c1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with N-methyl-4-(trifluoromethyl)aniline (1191 mg, 6.80 mmol) using method A to give 4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid as a white solid. Yield: 385 mg (47%). 1H-NMR: 8.11 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 3.21 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([N:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([C:16]([S:18][CH3:19])=N)[N:8]=[C:7]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:3]#[C:4][CH3:5].C([OH:35])C>>[CH2:2]([N:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([C:16]([S:18][CH3:19])=[O:35])[N:8]=[C:7]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:3]#[C:4][CH3:5]
Reactant: CCO
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=N)SC)c1C(=O)OCC
Agent: Cl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=O)SC)c1C(=O)OCC
Temperature: 60 °C
Reaction time: 15 h

Procedure:
5 ml of a 2N aqueous solution of hydrochloric acid was added to a 30-ml ethanol solution of 0.55 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-methyl sulfanylcarbonimidoyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was heated at 60° C. for 5 hours. After the reaction solution had been concentrated under reduced pressure, 25 ml of ethyl acetate and 1N sodium hydroxide solution were added thereto. The aqueous layer was extracted with 25 ml of ethyl acetate, and the organic layers were combined together. The mixture was washed with 10 ml of a saturated sodium chloride solution containing 1 ml of 1N sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, and 0.10 ml of triethylamine and 0.256 g of di-t-butyl dicarbonate were added thereto. The mixture was stirred at room temperature for 15 hours, and then 25 ml of ethyl acetate was added thereto. The mixture was washed successively with 10 ml of 0.1N hydrochloric acid, 10 ml of a saturated sodium bicarbonate solution, and 10 ml of a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.15 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (4:1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[C:4](=O)[NH:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:6]12[CH2:8][CH2:9][CH:3]([CH:2]([OH:1])[CH2:7]1)[CH2:4][NH:5]2
Reactant: O=C1NC2CCC1C(O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CC2CCC1CN2
Temperature: 25 °C
Yield: 139.8 %

Procedure:
To a solution of 5-hydroxy-2-aza-bicyclo[2.2.2]octan-3-one (2.6 g, 18 mmol) in 60 ml of anhydrous THF was added 55 ml of LAH (1.0 M in THF). After the mixture was refluxed under N2 for 24 h, it was cooled to rt and quenched with 2 ml of water, followed by 2 ml of 15% NaOH and 6 ml of water. The suspension was then stirred with MgSO4 and filtered. The filtrate was acidified with 1.0 M of HCl in ether and then concentrated to afford 3.2 g of 2-aza-bicyclo[2.2.2]octan-5-ol as the HCl salt.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:5].[Br-].[CH2:20]1[CH2:24]OC[CH2:21]1>>[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]1)(=[O:5])[C:21]#[C:20][CH3:24]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: C1CCOC1
Agent: [Br-]
Product: CC#CC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirred mixture of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2 g, 7.75 mmol) in dry THF (10 mL) was added 1-propynylmagnesinm bromide (30 mL, 15 mmol) under N2 at −78° C. The reaction mixture was stirred at −78° C. for 0.5 h, allowed to warm to rt slowly and stirred for another 10 h. The mixture was quenched with 2 N aq HCl (20 mL) at 0° C. and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (PE/EA=1:1) to afford tert-butyl 3-(but-2-ynoyl)pyrrolidine-1-carboxylate (1.6 g, 86%) as a white oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13](=[O:25])[CH:14]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:15].[Br:26][CH2:27][CH2:28][CH2:29]Br>O1CCCC1>[CH3:11][O:12][C:13](=[O:25])[C:14]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])=[O:18])([CH3:15])[CH2:29][CH2:28][CH2:27][Br:26]
Reactant: COC(=O)C(C)S(=O)(=O)c1ccccc1
Reactant: BrCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(CCCBr)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 6.6 ml, 6.6 mmol) was added dropwise to a stirred solution of 2-benzenesulfonylpropionic acid methyl ester (1.38 g, 5.7 mmol) in tetrahydrofuran at −78° C. The mixture was stirred for 30 min. and 1,3-dibromopropane (3.17 ml, 31.2 mmol) was added. The mixture was slowly warmed to room temperature and stirred for 4 days. After quenching with satd. aqueous NH4Cl, the mixture was extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified on silica gel (i-hexane-ethyl acetate 5–20%) to give the title product (330 mg, 15%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[C:4]([F:21])[CH:3]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH:29]1([C:26]2[CH:25]=[N:24][C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]4)=[C:4]([F:21])[CH:3]=3)=[N:28][CH:27]=2)[CH2:31][CH2:30]1
Reactant: Clc1ncc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(C4CC4)cn3)cc2F)C1
Temperature: 120 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
(R)-tert-Butyl 2-(4-amino-2-fluorophenyl)morpholine-4-carboxylate (300 mg), 2-chloro-5-cyclopropylpyrimidine (188 mg, CAS 166740-44-9) and cesium carbonate (495 mg) were combined with dioxane (8 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (35.1 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (31.4 mg) were then added. The reaction mixture was then capped and stirred at 120° C. for 3 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 55% EtOAc in hexanes) to afford (R)-tert-butyl 2-(4-(5-cyclopropylpyrimidin-2-ylamino)-2-fluorophenyl)morpholine-4-carboxylate (180 mg, 43%) as a yellow solid. MS (ISP): 415.2 ([M+H]+).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:46][CH3:47])=[C:21]([NH:24][C:25](=[O:45])[CH:26]=[CH:27][CH2:28][N:29]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:30][CH2:31]OS(C)(=O)=O)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.O>CN(C)C=O>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:46][CH3:47])=[C:21]([NH:24][C:25](=[O:45])[CH:26]=[CH:27][CH2:28][N:29]([CH2:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:30][CH2:31][S:3][C:1](=[O:4])[CH3:2])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC([O-])=S
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN(CCOS(C)(=O)=O)CC(=O)OC(C)(C)C
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN(CCSC(C)=O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
34 mg of potassium thioacetate are added to 150 mg of 4-[(3-bromophenyl)amino]-6-[(4-(N-[(tert-butyloxycarbonyl)methyl]-N-[2-(methylsulphonyloxy)ethyl]amino}-1-oxo-2-buten-1-yl)amino]-7-methoxy-quinazoline in 1 ml of dimethylformamide at ambient temperature. The reaction mixture is stirred overnight at ambient temperature and then combined with water for working up. The aqueous phase is separated off and extracted with ethyl acetate, the combined organic phases are dried over magnesium sulphate and freed from solvent in the rotary evaporator. Yield: 20 mg (14% of theory), Rf value: 0.62 (silica gel, ethyl acetate/methanol=15:1) Mass spectrum (EI): m/z=643, 645 [M]+
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:31])[N:5]([C:28](=[O:30])[CH3:29])[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1.[C:32]1([C@@H:38]([CH3:42])[C:39]([O-:41])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cs+].[I-].[Na+].O>C(#N)C>[C:28]([N:5]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[C:15]([F:27])[CH:14]=2)[CH2:8]1)[C:4]([O:3][CH2:2][O:41][C:39](=[O:40])[C@@H:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:42])=[O:31])(=[O:30])[CH3:29]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Reactant: C[C@@H](C(=O)[O-])c1ccccc1
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
(R)-acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid chloromethyl ester (10) (0.40 g, 0.84 mmol), cesium 2(R)-phenyl-propionate (0.37 g, 1.31 mmol) and sodium iodide (0.13 g, 0.86 mmol) in acetonitrile (25 mL) are heated to reflux overnight. After cooling to RT, water is added and the reaction mixture is extracted with EtOAc and then with dichloromethane. The organic phases are washed separately with brine and then the organic layers are combined, dried over MgSO4, filtered, and conc in vacuo. The isolated residue is subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-5% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 81%. 1H NMR (400 MHz, DMSO-d6): δ 7.43-7.38 (m, 1H), 7.33 (t, 1H), 7.27-7.15 (m, 6H), 5.78-5.72 (m, 2H), 4.63-4.57 (m, 1H), 4.04-3.95 (m, 2H), 3.84 (q, 1H), 3.76-3.69 (m, 2H), 3.36-3.26 (m, partially obscured by water, 2H), 3.17-3.12 (m, 1H), 3.07-3.04 (m, 2H), 2.31 (d, 3H), 2.11 (q, 2H), 2.01-1.97 (m, 2H), 1.35 (d, 3H); MS-APCI (m/z+): 341, 385, 517, 591.