Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[C:6]1([S:12][CH3:13])[CH:11]=[CH:10]C=C[CH:7]=1.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[S:12]1[CH:13]=[CH:10][CH:11]=[C:6]1[CH2:7][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: CSc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)Cc1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a stirred solution of 143 mL of 1.4M n-BuLi (0.20 mol) in 55 mL of dry THF, was added dropwise at room temperature under a nitrogen atmosphere 24.8 g (0.20 mol) of thioanisole. Upon completion of the addition, the yellow mixture began to reflux spontaneously The mixture was stirred at room temperature for 3 hours. Upon addition of 21.84 g (0.20 mol) of chlorotrimethylsilane, the mixture again began to reflux spontaneously. After stirring at room temperature overnight, the mixture was quenched with 100 mL of 5% of HCl. The aqueous layer was separated, and the organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. The crude product was distilled to give 19.22 g (49%) of the colorless sulfide, bp 84°-86° C./0.3 Torr; 1H NMR (CDCL3) δ0.17 (s, 9H, Si(CH3)3), 2.13 (s, 2H, CH2S), 7.0-7.42 (m, 5H, phenyl).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]#[C:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[C:32]#[C:33][CH3:34]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OC)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine-4-carboxylic acid was prepared starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine-4-carboxylic acid ethyl ester (2.5 g, 5.15 mmol) dissolved in THF:methanol (3:1, 200 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 1.26 g (54%); off white solid; mp 223° C.; MS: 458 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:19][C:20]([OH:22])=[O:21])[C:9]2=[O:23])=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:6]([O:21][C:20](=[O:22])[CH2:19][N:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]1=[O:23])[CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)Cn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCOC(=O)Cn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1 g of [3-(4-chlorophenyl)-2-oxo-4-phenyl-4-imidazolin-1-yl] acetic acid are dissolved in a small amount of anhydrous chloroform. 0.7 g of thionylchloride are added thereto and the mixture is stirred at about 50° C. for 2 hours. The mixture is evaporated in a vacuum, the residue is mixed with a small amount of chloroform and 0.31 g of hexanol are added to the mixture. After stirring for one hour at room temperature, the CHCl3 -solution is first extracted with an NaHCO3 -solution and then with water. It finally is dried over Na2SO4. The CHCl3 -solution is evaporated, remaining hexanol is distilled off a high vacuum and the residue is further purified chromatographically on silicic acid gel using CHCl3 as eluant.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH:21]1[C:26](O)=[O:27])=[O:19])([CH3:16])([CH3:15])[CH3:14].P(C#N)([O-])(OCC)=O>O1CCCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH:21]1[C:26]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:27])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCSCC1C(=O)O
Reactant: C1CCNC1
Agent: CCOP(=O)([O-])C#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCSCC1C(=O)N1CCCC1
Reaction time: 1 h
Yield: 74 %

Procedure:
Triethylamine (3.1 ml), followed by a solution of pyrrolidine (2.0 ml) in 10 ml of tetrahydrofuran, was added at 0° C. under a stream of nitrogen to a solution of 5.0 g of 4-(t-butoxycarbonyl)thiomorpholine-3-carboxylic acid in 100 ml of tetrahydrofuran. After the mixture had been stirred for 1 hour, a solution of 3.6 g of ethyl cyanophosphate in 10 ml of tetrahydrofuran was added to the mixture and the mixture was stirred for 5 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to yield 4.61 g (74%) of 4-(t-butoxycarbonyl)-3-(pyrrolidine-1-carbonyl)thiomorpholine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][N:5]=1)[CH3:2].Br[C:20]1[N:25]2[CH:26]=[CH:27][N:28]=[C:24]2[C:23]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[N:22][CH:21]=1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.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>[CH3:42][N:39]1[CH2:40][CH2:41][N:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:29][C:23]3[C:24]4[N:25]([CH:26]=[CH:27][N:28]=4)[C:20]([C:8]4[CH:7]=[CH:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=4)=[CH:21][N:22]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)c3nccn23)ccn1
Temperature: 85 °C

Procedure:
A mixture of 2-ethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (97 mg, 0.31 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (100 mg, 0.259 mmol), Pd(PPh3)4 (29 mg, 0.026 mmol) and NaOtBu (99 mg, 1.0 mmol) in DMF (3 mL) and water (1 mL) is heated at 85° C. for 18 hours. After this time the reaction mixture is cooled to room temperature and the solvents removed in vacuo. The residue is chromatographed on silica gel, eluting with DCM followed by 96:4 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated to afford the title ethoxypyridine as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH:27]CC(OC(C)(C)C)=O)=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:36]([OH:42])([C:38](F)(F)F)=[O:37].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[C:26]([CH2:38][C:36]([OH:42])=[O:37])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH2:27])=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)CC(=O)c2ccc3ccccc3c2NCC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)CC(=O)c2c(CC(=O)O)cc3ccccc3c2N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][(1,1-dimethylethoxycarbonyl)methyl]aminonaphthalene (147 mg, 0.30 mmol) in CH2Cl2 (2.0 mL) was added TFA (3.0 mL). The resulting reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo to afford an oil, which was diluted with water (15 mL), adjusted to pH 4.5 by saturated NaHCO3, then extracted by ethyl acetate (3×15 mL). The organic layer was evaporated in vacuo to afford 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][carboxymethyl]-aminonaphthalene (90 mg) as a solid; NMR (CDCl3) 1.26 (t, 3), 3.24-3.30 (m, 2), 3.35-3.42 (m, 6), 3.57 (m, 2), 4.14 (q, 2), 4.52 (s, 2), 7.48 (d, 1), 7.58 (m, 2), 7.84-7.94 (m, 4) ppm.
Reaction SMILES: [CH3:1]OC(OC)COC.[CH3:9][C:10]1([CH3:18])[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH2:29])[CH:24]=[N:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[N:29]=[CH:1]/[CH:13]2[C:14](=[O:16])[O:15][C:10]([CH3:18])([CH3:9])[O:11][C:12]2=[O:17])[CH:24]=[N:25][C:26]=1[O:27][CH3:28]
Reactant: COCC(OC)OC
Reactant: COc1cc(N)cnc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: COc1cc(/N=C/C2C(=O)OC(C)(C)OC2=O)cnc1OC
Temperature: 100 °C

Procedure:
A round bottom flask was charged with 2-methoxyacetaldehyde dimethyl acetal (2076 μl, 2076 μmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (299 mg, 2076 μmol). The flask was fitted with a reflux condenser and the mixture was heated at 100° C. for 2 h under nitrogen. 5,6-Dimethoxypyridin-3-amine (320 mg, 2076 μmol) was added, and within a minute a solid had precipitated out of solution. The heterogeneous mixture was heated at 100° C. for 10 min. The mixture was cooled to RT and the solids were filtered and washed with hexanes. (E)-5-((5,6-dimethoxypyridin-3-ylimino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was isolated as a yellow/orange solid. MS [M+H]=309.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16](Cl)=[O:17])[CH:5]=[CH:4][C:3]1=2.[OH:20][C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=1)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25]>>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([O:20][C:21]3[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=3)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Cl)ccc21
Reactant: C=CCOC(=O)c1cccc(O)c1
Product: C=CCOC(=O)c1cccc(OC(=O)C=Cc2ccc3c(c2)C(C)(C)CCC3(C)C)c1

Procedure:
In a similar manner to that of Example 1(d), by reaction of 2.8 g (10 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyl chloride with 1.8 g (10 mmol) of allyl 3-hydroxybenzoate, 2.6 g (62%) of the expected allyl ester are obtained in the form of a colourless oil.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([CH2:15][O:16]C)=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1.ClCCl.O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:12])[CH3:13])[C:5]([CH:15]=[O:16])=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1
Reactant: CCOC(=O)c1cc(Br)n(COCC[Si](C)(C)C)c1COC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(Br)n(COCC[Si](C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To 450 g (1.15 mol) of ethyl 5-bromo-2-methoxymethyl-1-(2-trimethylsilylethoxymethyl)-1H-pyrrol-3-carboxylate obtained in Reference example 15-(e) were added 5.4 L of dichloromethane and 540 ml of water, and then, 363 g (1.60 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added to the mixture by dividing it into several portions at room temperature. The mixture was stirred at room temperature for 30 minutes, and then, refluxed for 6 hours. After completion of the reaction, 450 g of Celite and 2.5 L of toluene were added to the reaction suspension, the mixture was stirred at room temperature for 30 minutes, and insoluble material was removed by filtration. The organic layer obtained by separating the filtrate was washed successively with a saturated aqueous solution of sodium hydrogencarbonate, and with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 430 g of the title compound as a pale brownish oil substantially quantitatively.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:7]=1.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:6]2[N:5]=[N:4][C:3]([CH2:2][NH:1][C:42]([NH2:43])=[NH:37])=[N:7]2)=[O:30])[N:17]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1nnc(CN)n1)c1csc(N)n1)C(=O)O
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1nnc(CNC(=N)N)n1)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.4 %

Procedure:
To a solution of 2-(((Z)-(2-(((2R,3S)-2-((5-(aminomethyl)-2H-tetrazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (20 mg, 0.038 mmol) and pyrazole-1-carboxamidine hydrochloride (11.6 mg, 0.079 mmol). in DMF (376 μL) was added DIPEA (26.2 μL, 0.150 mmol). After stirring at rt for 12 h the solution was concentrated in vacuo. Toluene was added and it was reconcentrated (3×). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (11 mg, 45%) as a white powder. LCMS: Rt=0.31 min, m/z=575.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 7.49-7.04 (m, 5H), 6.74 (br s, 1H), 5.26 (br s, 1H), 5.14-5.07 (m, 1H), 4.98-4.90 (m, 1H), 4.65 (br s, 2H), 4.59-4.52 (m, 1H), 1.36 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[O:8][C:9]3[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=3[C:11]=2[CH2:12][CH2:13][NH:14][CH:15]=1)=[O:5])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24](Cl)=[O:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[O:8][C:9]3[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=3[C:11]=2[CH2:12][CH2:13][N:14]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([F:30])=[C:21]([F:20])[CH:22]=2)[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CNCCc2c1oc1ccccc21
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CCc2c1oc1ccccc21

Procedure:
In a manner similar to Step F of Example 32, but using the intermediate 6,7-dihydro-5H-10-oxa-7-azabenzo[a]azulene-9-carboxylic acid ethyl ester and 3,4-difluorobenzoyl chloride, the title compound was prepared; 1NMR (CDCl3): δ 7.46-7.53 (4H, m), 7.34 (2H, m), 7.25 (2H, m), 4.33 (2H, q), 4.21 (2H, t), 3.17 (2H, t), 1.32 (3H, t). MS (ES): 398 (MH+).
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][C:18]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[O:20])=[CH:21][CH:22]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CN(C)CCN
Reactant: O=C(O)CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: CN(C)CCNC(=O)CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Yield: 92 %

Procedure:
The title compound was prepared from 3-(4-(adamantan-1-yl)phenoxy)propanoic acid (0.2 g, 0.66 mmol) and N,N-dimethylethane-1,2-diamine (0.058 g, 0.66 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)phenoxy)-N-(2-(dimethylamino)ethyl)propanamide as a white solid (0.225 g, 91.4% yield).
Reaction SMILES: [CH3:1][S:2]([CH2:4][S:5][CH3:6])=[O:3].C([Li])CCC.CCCCCC.Br[CH2:19][CH:20]([CH2:39]Br)[O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.O>[C:35]([Si:22]([O:21][CH:20]1[CH2:39][C:4]([S:2]([CH3:1])=[O:3])([S:5][CH3:6])[CH2:19]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CSCS(C)=O
Reactant: CC(C)(C)[Si](OC(CBr)CBr)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CSC1(S(C)=O)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of (methylsulfinyl)(methylthio)methane (27.70 g, 223.0 mmol) in tetrahydrofuran (90 mL) at −10° C. was added dropwise, a solution of 2.5 M n-butyllithium in hexane (89.2 mL, 223 mmol). The mixture was stirred at −10° C. for 2 hours. It was then cooled to −78° C. and transferred by cannula in a slow manner to a solution of [2-bromo-1-(bromomethyl)ethoxy](tert-butyl)diphenylsilane (42 g, 93 mmol, from Step 1) in tetrahydrofuran (70 mL, 900 mmol) held at −78° C. The mixture was stirred with warming to room temperature over 2 nights. Water was added, and then the product was extracted with three portions of DCM. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography (eluting with a gradient from 0-100% ethyl acetate/hexanes) afforded desired product as a mixture of diastereomers (34.1 g, 88%). 1H NMR (300 MHz, CDCl3), diastereomers: δ 7.74-7.58 (m, 8H), 7.48-7.31 (m, 10H), 4.52 (tt, 1H), 4.42 (tt, 1H), 3.05-1.99 (m, 8H), 2.47 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H), 2.00 (s, 3H), 1.05 (s, 9H), 1.02 (s, 9H).
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[CH2:27][S:28]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]1[N:45]=[CH:44][N:43]=[C:42]([O:46][CH:47]3[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]3)[CH:41]=1)[CH2:35][CH2:34]2)(=[O:30])=[O:29]>ClCCl>[Cl:5][CH2:1][CH2:27][S:28]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]1[N:45]=[CH:44][N:43]=[C:42]([O:46][CH:47]3[CH2:48][CH2:49][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:51][CH2:52]3)[CH:41]=1)[CH2:35][CH2:34]2)(=[O:30])=[O:29]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCO)ccc43)ncn2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCCl)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Carbon tetrachloride (58 μL, 0.601 mmol) and triphenylphosphine (52 mg, 0.198 mmol) were added to a dichloromethane (5 mL) solution of the tert-butyl 4-[(6-{5-[(2-hydroxyethyl)sulfonyl]indolin-1-yl}pyrimidin-4-yl)oxy]piperidine-1-carboxylate (49.9 mg, 0.0990 mmol) produced in Example 84, and the mixture was stirred overnight at room temperature. From the reaction solution, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-7:3, V/V) to obtain the title compound as white foam (32.3 mg, yield: 62%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O>[Cl:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Solvent: O
Product: O=[N+]([O-])c1cnc(N2CCOCC2)c(Cl)c1
Temperature: 120 °C

Procedure:
2,3-Dichloro-5-nitropyridine (Synthesis, 1990, 6, 499-501) (20 g, 104 mmol) was added portionwise to morpholine (40 mL) at 0° C. and heated at 120° C. for 1 h. The reaction was cooled to room temperature, water (100 mL) added and the reaction extracted with DCM (3×150 mL). The organics were dried (MgSO4), filtered, and the solvent removed under reduced pressure to give the product as a yellow solid, which was triturated with isohexane and allowed to dry under vacuum at 60° C. 1H NMR δ 8.98 (1H, d), 8.47 (1H, d), 3.74-3.69 (4H, m), 3.67-3.62 (4H, m); MS m/e MH+ 244.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[NH2:20]>C(O)(C)C>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1OC
Yield: 85.1 %

Procedure:
4-chloro-6,7-dimethoxy-quinazoline (1.50 g) and 3-choro-4-(m-fluoro-benzyloxy)-aniline (1.70 g) were dissolved into 150 mL of isopropanol. The mixture was reacted under reflux for 3 h, and a lot of yellow solid was deposited. The precipitated solid was filtered, and the filter cake was washed with cold ethanol and dried at 60° C. under vacuum overnight to obtain the title compound (2.50 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](OC(C)(C)C)=[O:11])[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4].Cl.[CH:29](N(C(C)C)CC)(C)C.C(OC(=O)C)(=O)C>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](=[O:11])[CH3:29])[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)OC)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (465 mg, 1.2 mmol) was dissolved in dichloromethane (1 mL) and HCl (4M dioxane, 3 mL) was added. The resultant suspension was stirred at room temperature for 30 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THF and diisopropyl ethylamine (154 mg, 1.2 mmol) was added, followed by acetic anhydride (122 mg, 1.2 mmol). The reaction was stirred at room temperature. After 30 minutes, all volatiles were removed in vacuo. The crude material was purified by silica gel chromatography (eluent: DCM/MeOH) to yield the product 1-Acetyl-3-(2-methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-4-carboxylic acid methyl ester (273 mg, 0.829 mmol): LCMS-ESI+: calc'd for C14H23N3O6: 329.4 (M+). Found: 330.4 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].[C:14]([OH:18])(=[O:17])[CH:15]=[CH2:16].[C:19]([OH:23])(=[O:22])[CH:20]=[CH2:21].[CH2:24]([C:26]([CH2:31][OH:32])([CH2:29][OH:30])[CH2:27][CH3:28])[OH:25].C([O-])(=O)C=C>C(O)(=O)C>[CH3:1][N:2]([CH2:11][CH2:10][C:9]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:1][N:2]([CH2:16][CH2:15][C:14]([OH:18])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:1][N:2]([CH2:21][CH2:20][C:19]([OH:23])=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:24]([C:26]([CH2:31][OH:32])([CH2:29][OH:30])[CH2:27][CH3:28])[OH:25]
Reactant: C=CC(=O)O
Reactant: CNc1ccccc1
Agent: C=CC(=O)[O-]
Agent: CCC(CO)(CO)CO
Solvent: CC(=O)O
Product: CN(CCC(=O)O)c1ccccc1

Procedure:
N-methylaniline (14.81 g) was added to glacial acetic acid (25 ml) containing trimethylolpropane triacrylate (16.05 g) and the mixture heated under reflux for 12 hr. The acetic acid was removed by distillation in vacuo to give a viscous oil. An infrared spectrum of the product showed that very few acrylate residues were present. Strong absorptions due to an ester and an aromatic amine group were present (1740 and 1600 cm−1).