Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]([NH:13][NH2:14])=[O:12].[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl[CH2:23]Cl>>[CH3:23][CH:10]([NH:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][CH:2]=1)[C:11]([NH:13][NH:14][C:15](=[O:17])[CH3:16])=[O:12]
Reactant: Cc1cccc(C)c1NCC(=O)NN
Reactant: ClCCl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NNC(=O)C(C)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 19.9 g (0.103 mol) alpha-(2,6-dimethylphenylamino)acethydrazide in 350 ml dichloromethane was added quickly 11.3 g (0.103 mol) acetic anhydride. A mild exotherm ensued. After being stirred at about 25° C. for about 16 hours, the reaction mixture was filtered to give 8.9 g of 1-(2,6-dimethylphenylaminoacetyl)-2-acetyl hydrazine, m.p. 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.S(Cl)([Cl:18])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([Cl:18])=[O:15]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)Cc1cc([N+](=O)[O-])cc(Cl)c1Cl

Procedure:
By the method of Example 1, Step E, 18.27 grams (0.073 mole) of 2,3-dichloro-5-nitrophenylacetic acid and 80 mL of thionyl chloride were reacted in 400 mL of carbon tetrachloride, yielding 20.90 grams of 2,3-dichloro-5-nitrophenylacetyl chloride. The NMR was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.Br[CH2:28][C:29]([NH2:31])=[O:30].CO>C(Cl)Cl>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Reactant: NC(=O)CBr
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(CC(N)=O)C3)ccc1OCC2

Procedure:
Following the procedure for 143, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with bromo acetamide and the crude product subjected flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 155 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1 H); 7.83 (d, J=2.18 Hz, 1 H); 7.24 (d, J=2.21 Hz, 1 H); 7.18 (d, J=8.31 Hz, 1 H); 6.86 (s, 1H); 5.71-5.63 (m, 1 H); 5.45 (s, 1 H); 4.54 (t, J=5.98 Hz, 2 H); 3.87 (t, J=7.28 Hz, 2 H); 3.81-3.72 (m, 1 H); 3.38 (t, J=6.84 Hz, 2 H); 3.22 (s, 2 H); 3.16 (t, J=5.99 Hz, 2 H); 1.59 (d, J=6.62 Hz, 6 H). 1 Exchangeable proton not observed. LCMS: RT=5.84 min, M+H+=408
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[P:29](Cl)([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32].C([Li])CCC>>[C:9]1([P:8]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[P:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12
Reactant: CCOP(Cl)OCC
Agent: [Li]CCCC
Product: CCOP(OCC)c1ccccc1P(c1cccc2ccccc12)c1cccc2ccccc12

Procedure:
For example, 2-bromophenol (4) is reacted with trifluoromethanesulfonic anhydride to form 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), which is then reacted with di(1-naphthyl)phosphine in the presence of a palladium complex catalyst to obtain (2-bromophenyl)[di(1-naphthyl)]phosphine (6). Next, the compound (6) is reacted with diethyl chlorophosphite in the presence of n-butyllithium to obtain diethyl 2-[di(1-naphthyl)phosphino]phenylphosphonite (7). Then, the compound (7) is reduced with lithium aluminum hydride in the presence of chlorotrimethylsilane to form [2-[di(1-naphthyl)phosphino]phenylphosphine (8). Thereafter, in the presence of n-butyllithium, the compound is reacted with dimesylate of (2R,5R)-2,5-hexanediol producible, for example, according to the method described in a literature (Tetrahedron: Asymmetry, 1991, 2, 569), whereby the aimed (S,S)-Me-UCAP-(1-Nap) (3) can be produced in a high efficiency.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[Cl:3][C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[CH:8]=[O:9]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCCCC1
Product: O=CC1=C(Cl)CCCC1
Temperature: 25 °C
Yield: 217.4 %

Procedure:
Phosphoryl trichloride (125 g, 815 mmol) was added dropwise into a flame-dried bottom flask containing N,N-dimethylformamide (74.5 g, 1019 mmol) at 0° C. with stirring. After addition, the mixture was warmed to ambient temperature for 30 min, and re-cooled to 0° C. before the dropwise addition of cyclohexanone (50 g, 509 mmol). The mixture was warmed to room temperature for 12 h. The reaction was poured over ice and quenched with NaHCO3. Once neutralized, the mixture was extracted with ethyl acetate (100 mL×3) and washed with water and brine. The organic phase was dried, filtered, and concentrated to afford the product (160 g, 87% yield). 1H NMR: (CDCl3, 400 MHz) δ 1.74˜1.75 (m, 2H), 1.76˜1.78 (m, 2H), 2.24˜2.27 (m, 2H), 2.53˜2.59 (m, 2H), 7.25 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3](=[N:10][OH:11])([NH2:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:12]1([C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:19]2[CH2:24][CH:23]([C:25](OC)=O)[CH2:22][N:21]=[CH:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:35]1([C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:19]2[CH2:24][CH:23]([C:25]3[O:11][N:10]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:9]=3)[CH2:22][N:21]=[CH:20]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: CCCCCC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Prepared by a procedure similar to Example 9, where sodium hydride (95% 40 mg, 1.7 mmol) and n-hexanamidoxime (217 mg, 1.7 mmol) were suspended in dry THF in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (640 mg, 1.7 mmol) was added, dissolved in dry THF and reflux continued 18 hours. The solvents were evaporated in vacuo and the residue was chromatographed (silica, chloroform/methanol, 9:1) to yield 1-triphenylmethyl-1,4,5,6-tetrahydro-5-(3-n-pentyl-1,2,4-oxadiazol-5-yl)pyrimidine. This product was dissolved in triflouroacetic acid (2 mL), with stirring at room temperature for 24 hours. The yellow solution was then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 110 mg (19%) white crystals, mp 97°-99° C. identified by 300 MHz nmr.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12](=[S:14])[NH2:13])[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3].[CH2:29](Cl)Cl.CI>CO>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12]([S:14][CH3:29])=[NH:13])[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3]
Reactant: ClCCl
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Solvent: CO
Solvent: CI
Product: CSC(=N)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.120 g, 0.29 mmol) in 2 mL of a 4:1 mixture of DCM:MeOH was added methyl iodide (0.022 mL, 0.34 mmol). After stirring for 16 hours at room temperature, methyl iodide (0.050 mL) was added and the mixture stirred for a further 4 hours then concentrated in vacuo. The residue was partitioned between saturated NaHCO3 (10 mL) and EtOAc (10 mL) and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (10-20% ethyl acetate/hexanes) to afford the desired product, 0.124 g, 59%.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][C:15]([S:17](=[O:22])(=[O:21])[N:18]([CH3:20])[CH3:19])=[CH:16][C:4]=2[CH2:3]1.[N:23]1([CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][O:33][C:32]2=[O:36])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[CH3:19][N:18]([CH3:20])[S:17]([C:15]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([N:26]3[CH2:27][CH2:28][N:23]([CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][O:33][C:32]4=[O:36])[CH2:24][CH2:25]3)[CH2:3][C:4]=2[CH:16]=1)(=[O:22])=[O:21]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(Cl)c1ccccc1S2
Reactant: O=C1OCCN1CCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1ccccc1S2

Procedure:
11.9 g of 10-chloro-10,11-dihydro-2-dimethylsulphamoyldibenzo[b,f]thiepin in 250 ml of chloroform are treated with 20 g of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and the mixture is heated under reflux for 24 hours. Then the mixture is evaporated under reduced pressure and the residue taken up in ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is dissolved in benzene and filtered through a column filled with 100 g of aluminium oxide (activity stage II). The eluate is evaporated and, for the purpose of further purification, chromatographed on 75 g of silicagel (0.2-0.5 mm), elution being effected with a 1:1 mixture of chloroform saturated with concentrated ammonia/carbon tetrachloride. The purified product is recrystallised from ethyl acetate/petroleum ether. There is obtained 3-[2-[4-{10,11-dihydro-2-dimethylsulphamoyl-dibenzo[b,f]thiepin-10-yl}-1-piperazinyl]-ethyl]-2-oxazolidinone which melts at 164°-165° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[N:3]=1.CO.[Br-:24].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCCl>[Br:24][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[NH2:11])[N:4]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[N:3]=[C:2]2[CH3:1]
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3ccc(N)cc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(N)cc32)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 147.7 %

Procedure:
3-Methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-ylamine (301 mg, 1.0 mmol) was dissolved in 1,2-dichloroethane (80 ml) and methanol (40 ml) at room temperature. The mixture was heated to 80° C. and then the tetrabutylammonium tribromide (1.0 eq, 482 mg) was added. Stirring was continued for 10 minutes, and then the mixture was partitioned between diethyl ether and saturated aqueous sodium sulfite solution. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 hexanes/ethyl acetate) to give 5-bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-ylamine (280 mg, 73.7%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:12]([O-])=O)[C:5]([NH:15][CH:16]([CH2:18]C(OCC)=O)[CH3:17])=[CH:4][CH:3]=1.[Sn](Cl)Cl.[C:27](OCC)(=[O:29])C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[C:5]([NH:15][C:16]([CH3:17])([CH3:18])[C:27](=[O:29])[NH:12]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)Nc1ccc(Br)c(C(=O)OC)c1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1c(Br)ccc2c1NC(=O)C(C)(C)N2
Yield: 70 %

Procedure:
Methyl 6-bromo-3-[(2-ethoxycarbonyl)propan-2-yl]amino-2-nitrobenzoate (Reference Compound No. 1-(5), 105 mg, 0.26 mmol) was dissolved in anhydrous ethanol (4.5 mL), tin (II) chloride (247 mg, 1.30 mmol) was added thereto, and then the reaction mixture was refluxed for 5 hours. After the reaction mixture was cooled down, ethyl acetate (25 mL) was added thereto, the mixture was neutralized with aqueous sodium hydrogen carbonate solution, and then filtered on celite. After the filtrate was partitioned, the water layer was extracted with ethyl acetate (10 mL, 2 times), the combined organic layer was washed with water (50 mL, 2 times) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (56.3 mg) as a pale yellow solid. (Yield 70%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.O=[C:18]([CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH2:26][CH3:27])[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]12
Reactant: COc1ccccc1C=O
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2OC)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:19]=1.OCC1C=CC2C=CC3C=CC=CC=3SC=2C=1>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:9]2[S:8][C:7]3[CH:19]=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][C:6]=3[CH:12]=[CH:11][C:10]=2[CH:13]=1
Reactant: COc1ccc2c(c1)C=Cc1ccc(CO)cc1S2
Agent: OCc1ccc2c(c1)Sc1ccccc1C=C2
Product: COc1ccc2c(c1)C=Cc1ccc(C=O)cc1S2

Procedure:
Repeat the procedure of Example 4, substituting an equivalent quantity of 3-hydroxymethyl-8-methoxydibenzo[b,f]thiepin for the 3-hydroxymethyldibenzo[b,f]thiepin to obtain the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1O.BrC1C=C([N+]([O-])=O)C=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=[N+]([O-])c1cccc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2Br)CC1
Temperature: 25 °C
Reaction time: 11.5 h
Yield: 88.6 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (2.7 g), 3-bromo-4-hydroxynitrobenzene (1.9 g) [which was prepared from 3-bromonitrobenzene according to the method described in J. Org. Chem., 63 4199 (1998)] and triphenylphosphine (4.4 g) in dichloromethane (50 ml) was added dropwise diethyl azodicarboxylate (2.7 ml) and the mixture was stirred at room temperature for 11.5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (3.1 g, yield 91%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28])([O-:23])=[O:22].Cl>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][N:7]1[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CSCCN1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CSCCN1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of thiomorpholin-3-ylcarboxylic acid ethyl ester (5.05 g) in methylene chloride (120 mL) were added dimethylaminopyridine (352 mg), triethylamine (4.9 mL) and 3-nitrobenzoyl chloride (5.62 g) in ice bath and then the mixture was stirred at room temperature overnight. 2N hydrochloric acid was added to the reaction mixture, which was extracted with methylene chloride. The extract was wash with a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (5.91 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+].CN(C)[CH:18]=[O:19]>>[CH3:18][O:19][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:2]1[CH:11]=[C:10]([O:19][CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: CN(C)C=O
Agent: [Na+]
Product: COc1cc(Cl)c2ccccc2n1
Product: COc1cc(OC)c2ccccc2n1

Procedure:
2,4-Dichloroquinoline (cf. example 14) (4.4 g), sodium methoxide (5.4 g) and dimethyl formamide (70 ml) were heated together at 70° for 2 hrs. The reaction mixture was partitioned between water and ethyl acetate and worked up in standard fashion. The crude product was purified by column chromatography on silica (10% ether in hexane) to give 2-methoxy-4-chloroquinoline (0.87 g) and 2,4-dimethoxyquinoline (1.8 g). The latter was subjected to aqueous hydrolysis by 6N hydrochloric acid for 3 hrs at reflux temperature to give 2-hydroxy-4-methoxyquinoline. This was converted to 2-chloro-4-methoxyquinoline.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[F:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cc(F)ccc2F)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cc(F)ccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
A solution of (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.35 g, 0.70 mmol) in methanol (7.1 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (20 mg, 0.10 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (000 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2-5% methanol/dichloromethane) afforded (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.23 g, 71%) as a pale orange solid: HR-ES-MS m/z calculated for C22H26N4O5F2 [M+H]+ 465.1944, observed 465.1943; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H), 1.43 (br. s., 1H), 1.48-1.63 (m, 1H), 1.66-1.82 (m, 1H), 3.18-3.31 (m, 2H), 3.66-3.79 (m, 1H), 3.84 (dd, J=13.4, 7.5 Hz, 1H), 4.07 (dd, J=13.4, 3.6 Hz, 1H), 4.20 (d, J=18.4 Hz, 1H), 4.58 (d, J=18.4 Hz, 1H), 4.69 (t, J=5.6 Hz, 1H), 4.86 (dd, J=10.7, 4.7 Hz, 1H), 4.92 (d, J=5.4 Hz, 1H), 5.01 (s, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.15-7.32 (m, 1H), 7.43-7.60 (m, 3H), 10.76 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reaction time: 4 h
Yield: 40.6 %

Procedure:
To a stirred solution of 2-(6-chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.080 g, 165 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.88 g, 1.27 mL, 16.5 mmol). The reaction mixture was stirred for 4 h, then was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated in vacuo again, then was suspended in dichloromethane and ethylenediamine (743 mg, 0.835 mL, 12.4 mmol) added. After 15 h the mixture was concentrated, triturated with water and the solid obtained by filtration was dried and purified by chromatography (silica, SiliCycle 25 g cartridge, 0-5% methanol in dichloromethane, gradient over 15 min) to give 2-(6-chloro-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (24 mg, 67.0 μmol, 41%) as a pale yellow powder. MS (M+Na)+=377; 1H NMR (DMSO-d6) δ: 13.16 (br. s, 1H), 12.39 (br. s, 1H), 9.12 (s, 1H), 8.39 (d, J=8.7 Hz, 1H), 8.17 (d, J=2.6 Hz, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.53 (s, 1H), 7.09 (dd, J=9.1, 1.0 Hz, 1H), 4.18-4.41 (m, 1H), 1.31 (d, J=6.4 Hz, 6H)
Reaction SMILES: C=C.[C:3](=[O:6])([OH:5])[OH:4].[CH:7]([CH:9]=[CH2:10])=[CH2:8]>>[CH2:7]=[CH2:8].[C:3]1(=[O:5])[O:4][CH2:10][CH:9]([CH:7]=[CH2:8])[O:6]1
Reactant: O=C(O)O
Reactant: C=CC=C
Agent: C=C
Product: C=CC1COC(=O)O1
Temperature: 23 °C
Reaction time: 28 h

Procedure:
A 200 mL flame dried pear-shaped Schlenk flask equipped with a magnetic stir bar and capped with a septum was charged with (2,6-di-isopropylphenylimino)-1,4-dithiane Pd(II) catalyst XII (100 mg) in an argon filled glove box. Upon removal from the glove box, the flask was evacuated and backfilled with ethylene. The catalyst was dissolved in CH2Cl2 (20 mL) and immediately treated with vinyl ethylene carbonate (10 mL). The resulting orange solution was stirred at 23° C. under an ethylene atmosphere (1 atm) for 28 hours. A small amount of polymer had precipitated out of solution. The polymerization was quenched with MeOH and acetone leaving gray oil adhering to the walls of the flask. The polymer was dissolved in CH2Cl2 and transferred to a storage jar. The solvent was left to evaporate and the resulting oily polymer. The polymer was washed several times with acetone and MeOH to remove any remaining monomer and was dried in vacuo at ~80° C. for 1 day to afford a tacky solid (1.15 g, 613 TO). 1H NMR was consistent with a copolymer containing approximately 95.5 weight % ethylene and 4.5 weight % vinyl ethylene carbonate monomer units.; Mn 15,400 g /mol ; Mw 96,000 g /mol ; DSC Tg -64° C., Tm -31° C.