Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CNS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
A solution of 18.1 g (0.14 mole) of N-methylsulfamoyl chloride (Example 2, pt. a) in 20 ml methylene chloride was added at 10°-20° C. to a solution of 12.8 g (0.10 mole) of 4-chlorophenol and 15 g (0.15 mole) of triethylamine in 50 ml of methylene chloride. The cooling was removed and the mixture stirred at ambient temperature for four hours. The mixture was filtered to remove the triethylamine hydrochloride. The filtrate was extracted with dilute HCl (6 ml of 37% hydrochloric acid in 60 ml water) followed by a water wash. The organic layer was then extracted with dilute potassium carbonate (8.0 g in 80 ml water) followed by a water wash. The methylene chloride layer was concentrated to 21.7 g of yellow oil which crystallized on cooling. The solid was stirred in a mixture of 10 ml toluene and 63 ml petroleum ether to obtain 20.3 g of yellow solid. The 20.3 g was recrystallized from 1:2 toluene: petroleum ether to give 8.73 g of white solid, mp 61°-62° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([NH:8][CH2:9][C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])([CH3:7])[CH3:6].[CH:19](OC1C=CC([N+]([O-])=O)=CC=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:10](=[O:11])[CH2:9][NH:8][C:5]([CH3:7])([CH3:6])[CH2:4][NH:3][CH:19]=[O:20])#[N:18]
Reactant: CC(C)(CN)NCC(=O)N1CCC[C@H]1C#N
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(CNC=O)NCC(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
(S)-1-[(2-Amino-1,1-dimethylethyl)aminoacetyl]-pyrrolidine-2-carbonitrile dihydrochloride (1.48 g) was dissolved in acetonitrile (50 ml), and 4-nitrophenyl formate (1.00 g) and potassium carbonate (1.37 g) were added thereto and stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 5:1) to give (S)-N-{2-[2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methyl-1-propyl}-formamide (693 mg, Y.:55%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[NH:29][C:10]2=[N:11][C:12]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:14]=[C:9]2[CH:8]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[N:29]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:10]2=[N:11][C:12]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:14]=[C:9]2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2[nH]1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1c(CCOC(C)=O)cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2,3-Dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethyl acetate (step 3) (12 mg, 0.031 mmol) was dissolved in dry DMF (1 ml) at RT and treated with K2CO3 (12.91 mg, 0.093 mmol) and ethyl 7-bromoheptanoate (0.012 ml, 0.062 mmol). The resulting brown suspension was stirred at RT for 16 hours. The mixture was then heated at 60° C. for 5 hours and after cooling to RT, stirred overnight. The mixture was added to water (30 ml) and extracted with DCM (×3). The combined organic extracts were passed through a phase separating column and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:6]2[O:10][CH2:9][C:8](=[O:11])[C:7]=2[CH:12]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[CH:28]1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:9]2\[O:10][C:6]3[C:5]([CH2:13][N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=3[C:8]\2=[O:11])=[CH:28]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)C(=O)CO2
Solvent: CO
Solvent: C1CCNCC1
Product: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)C(=O)/C(=C/c1c[nH]c3ccccc13)O2
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A solution of tert-butyl 4-((5-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl)piperazine-1-carboxylate (0.024 g, 0.066 mmol) in methanol (2.0 mL) was added with 1H-indole-3-carboxaldehyde (0.011 g, 0.073 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-5-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.027 g, 84%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH2:9][OH:10])([CH3:6])([CH3:5])[CH3:4].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1>C1(C)C=CC=CC=1.O>[C:3]([O:7][CH2:8][CH2:9][O:10][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([Br:11])[N:13]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OCCO
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OCCOc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (6.8 g, 60% dispersion in mineral oil, 0.169 mol) was added portionwise to an ice-cold solution of 2-(tert-butoxy)ethanol (20.0 g, 0.169 mol) in toluene (500 ml) under nitrogen, and the solution stirred for 30 minutes whilst warming to ambient temperature. 2,6-Dibromopyridine (40.0, 0.169 mol) was added, and the reaction heated under reflux for 3 hours. The mixture was allowed to cool to ambient temperature and was diluted with water (100 ml), and extracted with ethyl acetate (2×400 ml). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a yellow oil (quantitative). 1H nmr (CDCl3, 400 MHz) δ: 1.21 (s, 9H), 3.67 (t, 2H), 4.40 (t, 2H), 6.68 (d, 1H), 7.05 (d, 1H), 7.38 (t, 1H). LRMS: m/z 296/298 (M+23)+.
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][CH2:32][CH2:33][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.[OH-].[Na+]>CO>[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)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OC)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-n-Butoxy-benzenesulfonyl) 1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylic acid ethyl ester (3.0 g, 6.1 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.5 g (53%). white solid mp 207° C., MS: 462.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[CH3:14][S:13][C:4]1[N:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of 5.0 g (21.49 mmol) of ethyl 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate and 4.9 mL (53.72 mmol) of aniline in 75 mL of THF are added 7.49 mL (53.72 mmol) of triethylamine. The mixture is stirred at room temperature overnight. After evaporating off the THF, aqueous 1N HCl solution is added and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated aqueous NaHCO3 solution and then with NaCl solution. The organic phase is dried over MgSO4. After filtering, the filtrate is concentrated to give 3.99 g of the expected product in the form of a beige-coloured solid, which is used as obtained in the following step. Yield=64%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[CH2:6][CH2:5]2.[CH2:15](OB(C=C)OCCCC)[CH2:16]CC.C([O-])([O-])=O.[Na+].[Na+]>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.C1COCC1.O>[N+:11]([C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:14])=[CH:3][C:2]=1[CH:15]=[CH2:16])([O-:13])=[O:12]
Reactant: O=C1CCc2cc(Br)c([N+](=O)[O-])cc21
Reactant: C=CB(OCCCC)OCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Yield: 77 %

Procedure:
A solution of 5-bromo-6-nitro-indan-1-one (58 mg, 0.23 mmol), (J. Med. Chem., 2003, 46, 399-408), vinylboronic acid dibutyl ester (74 μL, 0.34 mmol), Pd(PPh3)2Cl2 (7.8 mg, 0.0011 mmol), and Na2CO3 (167 mg, 1.57 mmol) in 4:1 THF/H2O (1.4 mL/360 μL) was heated to 80° C. overnight. The crude reaction was filtered over Celite and extracted with EtOAC. The organic phase was dried (MgSO4), filtered, and concentrated. The crude material was chromatographed (SiO2) to afford 36 mg (79%) of 6-Nitro-5-vinyl-indan-1-one; LC/MS calculated for [M+H]+ C11H9NO2: 204.1, found: 204.1.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
Methyl (4-nitrophenoxy)acetate 7 (100 g, 474 mmol) was refluxed in conc. HCl (1 L) for 8 hours. The reaction mass was cooled to room temperature and crude 22 was filtered, dried and recrystallised from a mixture of ethyl acetate:hexane (1:5) to give pure 22 (86 g, 92.1%) as a white shining powder with an m.p. between 186-188.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCC3CO3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: C1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCC(O)CN3CCCCC3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 60 °C
Reaction time: 72 h
Yield: 70.3 %

Procedure:
4-Chloro-5-(2,3-epoxypropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (44.9 mg, 0.081 mmol) was dissolved in N,N-dimethylacetoamide (1.0 mL), and the solution was added with piperidine (0.160 mL, 1.61 mmol), followed by stirring at 60° C. for 72 hours. The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[2-hydroxy-3-(piperidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (36.3 mg, yield 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)C(O)=O.C(Cl)(=O)C(Cl)=[O:14].Cl.CNC.[CH3:22][N:23]([CH3:25])[CH3:24]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[CH:6][C:10]=1[C:22]([N:23]([CH3:25])[CH3:24])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C
Reactant: Cc1ccc(Cl)cc1C(=O)O
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(C(=O)N(C)C)c1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of 5-chloro-2-methylbenzoic acid (10 g, 58.6 mmol) dichloromethane (100 ml), cooled in an ice bath, was added a solution of oxalyl chloride in dichloromethane (2 M, 33 ml, 66 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 2 hours, dimethylamine hydrochloride (9.5 g, 116 mmol) was added followed by a solution of trimethylamine (25 ml, 180 mmol) in dichloromethane (100 ml) slowly. After stirring for 3 hours, the mixture was concentrated under reduced pressure and partitioned between ethyl acetate (200 ml) and hydrochloric acid (1 M, 200 ml). The organic layer was concentrated under reduced pressure to afford 2-chloro-5, N,N,-trimethyl benzamide (11.6 g, 100% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:50])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=5[O:33][C@H:34]([CH2:36]C=C)[CH3:35])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:39])[C:12]=2[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:46]([O:45][C@@H:40]([C:12]1[C:13]([CH3:39])=[CH:14][C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:50])([O:4][CH2:1][CH:2]=[CH:3][CH2:36][C@H:34]([CH3:35])[O:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:41]([O:43][CH3:44])=[O:42])([CH3:49])([CH3:47])[CH3:48]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(F)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Yield: 93 %

Procedure:
Prepared in 93% yield from methyl(S)-2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate. LCMS (ESI, M+1): 656.3.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH2:31][OH:32])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH:31]=[O:32])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reaction time: 0.5 h

Procedure:
A solution of dimethyl sulfoxide (3.6 ml, 50.7 mmol) in methylene chloride (15 ml) was dropwise added to a solution of oxalyl chloride (2.89 ml, 33.9 mmol) in methylene chloride (100 ml) in a nitrogen stream at -78° C. The reaction solution was stirred at the same temperature for 30 minutes. To this mixture, a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-hydroxymethylpyrrolidine (8.0 g, 24.2 mmol) in methylene chloride (50 ml) was dropwise added at -78° C. This mixture was stirred at the same temperature for 30 minutes, and then triethylamine (11.1 ml, 79.8 mmol) was added thereto. The mixture was stirred further for 30 minutes. The reaction mixture was poured into methylene chloride (200 ml), and the organic layer was washed sequentially with dilute hyrochloric acid, water and a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily residue of (2S,4 R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-formylpyrrolidine.
Reaction SMILES: N1CCC[CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=[O:12].[CH:15](=O)[CH3:16]>C(OCC)(=O)C>[CH2:2]([O:12][C:11](=[O:13])[C:10](=[CH:15][CH3:16])[C:9](=[O:14])[CH2:8][Cl:7])[CH3:3]
Reactant: CC=O
Reactant: O=C(O)CC(=O)CCl
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Product: CC=C(C(=O)CCl)C(=O)OCC

Procedure:
1 g of piperidine were dropped into a stirred mixture of 82 g of 4-chloroacetoacetic acid and 24 g of acetaldehyde at -20°. After stirring the mixture at -10° to -20° for 7 hours 100 ml of ethyl acetate were added and the solution was subsequently extracted three times with ice-cold 1 n hydrochloric acid and with water. The organic phase was dried over magnesium sulphate and concentrated. The oil which remained was subjected to Kugelrohr-distillation under a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH3:21][C:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH3:21][C:22]1([C:28]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=N)c1c(F)cccc1Cl
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=NC(=O)C1(C)CCCCC1)c1c(F)cccc1Cl

Procedure:
Ethyl 2-chloro-6-fluoro-benzimidate (1.61 g) and triethylamine (1.0 g) are dissolved in toluene (100 ml), to which is added dropwise 1-methylcyclohexylcarbonyl chloride (1.5 g) at 5°-10° C. with stirring and thereafter stirred at room temperature for 1 hour. Further, it is reacted at 80°-100° C. for 16 hours. After the completion of the reaction, the reaction solution is washed with a saline solution and further with water and then the resulting toluene layer is dried on sodium sulfate and concentrated to obtain crude product of ethyl N-(1-methylcyclohexylcarbonyl)-2-chloro-6-fluorobenzimidate.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:5]([CH2:6][CH2:7][OH:8])[N:4]([CH:9]2[CH:16]3[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)[C:3]1=[O:19].[H-].[Na+].Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1.O>O1CCCC1.CN(C)C=O>[CH3:1][C:2]1([CH3:20])[N:5]([CH2:6][CH2:7][O:8][C:24]2[N:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[N:4]([CH:9]2[CH:10]3[CH2:11][CH:12]4[CH2:13][CH:14]([CH2:15][CH:16]2[CH2:17]4)[CH2:18]3)[C:3]1=[O:19]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1CCOc1ccc(C#N)cn1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Under an argon atmosphere, a mixed solution of 4,4-dimethyl-1-(2-hydroxyethyl)-2-(adamantan-2-yl)-1,2-diazetidin-3-one (27.8 mg, 0.100 mmol) in tetrahydrofuran-N,N-dimethylformamide (2:1, 1 mL) was added with sodium hydride (10.0 mg, 0.200 mmol) and 6-chloro-3-pyridine carbonitrile (27.7 mg, 0.200 mmol), and the resultant was stirred at the same temperature for 1 hour. The reaction solution was added with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparatory Thin-Layer chromatography (hexane:ethyl acetate=1:1), and the title compound (38.1 mg, quant.) was obtained as a white crystalline powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:8][CH2:7]2.[C:32]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([CH2:40][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH2:10][CH:9]([N:12]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:8][CH2:7]3)=[CH:42][CH:43]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)CCCCN(Cc1ccc(C(=O)OC)cc1)C1CCc2cccc(O)c2C1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCN(Cc1ccc(C(=O)OC)cc1)C1CCc2cccc(OCc3ccc(C(C)(C)C)cc3)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
550 mg (1.29 mmol) of the compound from Example 3A were dissolved in 35 ml of DMF, 320 μl (1.6 mmol) of 4-tert-butylbenzyl bromide and 1.4 g (4.14 mmol) of cesium carbonate were added and the mixture was stirred at RT for 18 h. Water was then added, and the mixture was extracted repeatedly with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The crude product obtained was purified by preparative HPLC (method 1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:35]([C:29]3[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:28]=3[F:27])(=[O:37])=[O:36])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To a solution of 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (35 g, 89.5 mmol) in pyridine (400 mL), 2,6-difluorobenzene-1-sulfonyl chloride (20.9 g, 98.5 mmol) was added dropwise. The reaction was stirred at rt for 2 h. Then the reaction was washed with water (400 mL), and extracted with DCM (2×400 mL). The organic layer was washed with water, brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:2) to afford the title compound (18.5 g, 36.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (d, J=5.3 Hz, 1H), 7.65-7.70 (m, 1H), 7.40-7.50 (m, 1H), 7.25-7.30 (br, 1H), 7.18-7.23 (m, 2H), 6.88-6.98 (m, 2H), 6.38 (d, J=5.3 Hz, 1H), 3.72-3.80 (m, 4H), 3.50-3.58 (m, 4H); m/z (ES+): 568 [M+H]+.