Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[I:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([C:20](=[CH:23]NC1C=CC=CC=1)[C:21]#[N:22])=[O:19]>C(O)C.CO>[NH2:22][C:21]1[N:2]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=2[CH3:13])[C:7]([OH:9])=[O:8])[N:3]=[CH:23][C:20]=1[C:18](=[O:19])[C:17]1[CH:31]=[CH:32][CH:33]=[C:15]([I:14])[CH:16]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Reactant: Cc1ccc(C(=O)O)cc1NN
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Temperature: 75 °C
Yield: 22 %

Procedure:
To a stirred solution of 3-hydrazino-4-methyl-benzoic acid hydrochloride 1 (Example 3A, 314 mg, 1.54 mmol, 1.0 eq) in 50 mL of ethanol and 5 mL of methanol was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 2 (579 mg, 1.54 mmol, preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84). The mixture was heated to 75° C. for 18 h. The precipitated solids were collected on a fritted filter and were washed with ethanol to provide 3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-4-methyl-benzoic acid 3 (153 mg, 22%) as a white solid. MS m/z 448 [M+H]+; 1H NMR (300 MHz, DMSO-d6)<2.18 (s, 3H), 7.05 (bs, 2H), 7.34 (dd, J1=J2=7.7 Hz), 7.58 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.81 (m, 2H), 7.94 (m, 1H), 7.98 (m, 1H), 8.03 (m, 1H) ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=O)[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:8]=1.O=P(Cl)(Cl)[Cl:27].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:27][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:8]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(Cl)n1
Temperature: 120 °C
Yield: 58 %

Procedure:
4-(4-(2-(Methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl)pyrimidin-2-ylamino)benzonitrile (34) (700 mg, 2.081 mmol) was dissolved in POCl3 (1940 μl, 20.81 mmol), then the reaction mixture was heated at 120° C. for 3 hours. The reaction mixture was cooled to rt, then was slowly poured into an ice-cooled saturated Na2CO3 solution while stifling vigorously. The reaction mixture was then adjusted to pH 7 with additional Na2CO3 solution. DCM was added to the mixture and the aqueous layer was extracted twice with DCM. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo to obtain the desired product as a bright yellow solid (428 mg, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62 (s, 3 H) 7.39 (d, J=5.05 Hz, 1 H) 7.74 (m, 2 H) 8.00 (m, J=9.09 Hz, 2 H) 8.69-8.80 (m, 1 H) 8.93 (s, 1 H) 10.42 (s, 1 H). MS (ES+): m/z=355.3 (100) [MH+]. HPLC: tR=1.57 minutes over 3 minutes. Purity: 91% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[C:13]=2[O:20][CH3:21])[N:4]=1)[CH3:2].CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:25][CH3:24])[C:13]=2[O:20][CH3:21])[N:4]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCc1ccc(C#N)c(Oc2cccc(C=O)c2OC)n1
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1ccc(C#N)c(Oc2cccc(CNC)c2OC)n1
Yield: 62.7 %

Procedure:
6-Ethyl-2-(3-formyl-2-methoxy-phenoxy)-nicotinonitrile (0.28 g, 1.0 mmol), methylamine (33% in ethanol, 0.8 mL, 6.4 mmol) and sodium cyanoborohydride (80 mg, 1.3 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (60 mL) for 16 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.0 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 6-ethyl-2-(2-methoxy-3-methylaminomethyl-phenoxy)-nicotinonitrile difumarate (166 mg, 32%) as a beige solid.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:39][C@H:40]([C:45]([OH:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44]>C1COCC1>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([NH:39][C@H:40]([C:45]([OH:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:16])[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)[C@@H]1CS[C@H](c2ccccc2O)N1C(=O)CCSC(C)=O)C(=O)O
Yield: 22 %

Procedure:
The suspension of mixed anhydride in THF is prepared by using 5.3 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 1.5 g of N-methylmorpholine and 2.0 g of isobutyl chlorocarbonate. To the suspension the aqueous solution of 4.5 g of L-methionine and 3.0 g of N-methylmorpholine is added, and treated in the same manner as Example 1 to give 1.6 g (66%) of the titled compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:14]=2)[C:11](=[O:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:26])[N:4]=1.Cl[C:28]1[C:29]2[CH:36]=[CH:35][NH:34][C:30]=2[N:31]=[CH:32][N:33]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:31]1[C:30]2[NH:34][CH:35]=[CH:36][C:29]=2[C:28]([NH:1][CH2:2][C:3]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])[CH:14]=3)[C:11](=[O:25])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[F:26])[N:4]=2)=[N:33][CH:32]=1
Reactant: NCc1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: O=c1c2c(F)cccc2nc(CNc2ncnc3[nH]ccc23)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 36 h
Yield: 20.6 %

Procedure:
Under nitrogen, to 2-(aminomethyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (73 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (34 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 36 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 20 mg of the title compound (21% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: Ic1ccccc1-c1cnccn1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccc1-c1cnccn1
Yield: 39 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (145 mg, 0.47 mmol) and 2-(2-iodophenyl)pyrazine (0.11 g, 0.46 mmol) according to the methods of Example 6 Step 4. Purification by flash column chromatography eluting with a 10-60% ethyl acetate/isohexane gradient gave 2-(2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}phenyl)pyrazine (79 mg, 38%). 1H NMR (500 MHz, CDCl3) δ 8.77 (1H, d, J=1.2 Hz), 8.51 (1H, d, J=2.4 Hz), 8.44-8.38 (1H, m), 8.28-8.23 (1H, m), 8.03 (1H, s), 7.98 (1H, s), 7.87 (2H, t, J=8.8 Hz), 7.79 (1H, dd, J=1.6, 8.5 Hz), 7.74-7.62 (4H, m), 7.56 (1H, dd, J=1.7, 8.6 Hz), 7.42-7.35 (1H, m), 7.23-7.15 (2H, m); m/z (ES+) 441 [MH+].
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=O>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=[S:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1ccc(F)cc1F)c1ccccn1
Solvent: Cc1ccccc1
Product: Fc1ccc(NC(=S)c2ccccn2)c(F)c1
Yield: 94.7 %

Procedure:
Lawesson's reagent (29.8 g, 74 mmol) and N-(2,4-difluorophenyl)-2-pyridinecarboxamide (14.37 g, 61 mmol) were combined in toluene (185 mL) and refluxed for 3 hours. After evaporation of the solvent, the residue was dissolved in dichloromethane, preadsorbed on silica gel, and flash chromatographed (eluted with 2% ethyl acetate in petroleum ether) to provide N-(2,4-difluorophenyl)-2-pyridinecarbothioamide as a yellow solid (14.45 g, 94%) m.p. 124°-129° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(N)c1
Product: CC(=O)Nc1cccc(C)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
m-Toluidine (10 ml; 93 mmol) was added to a stirred solution of acetic anhydride (30 ml). The reaction mixture was stirred for 1,5 h at rt., evaporated to dryness, stirred with H2O and filtered to give 13 g product (94%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Mg].CN([CH:17]=[O:18])C>>[CH3:11][N:10]([CH3:12])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:17]=[O:18])=[CH:3][CH:4]=1
Reactant: CN(C)CCc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Mg]
Product: CN(C)CCc1ccc(C=O)cc1

Procedure:
2-(4-Bromophenyl)-N,N-dimethylethylamine (6.8 g) was refluxed under heating with magnesium for 1 hr to prepare a Grignard reagent, which was reacted with DMF to give the objective 4-(2-dimethylaminoethyl)benzaldehyde as an oil (4.2 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[C:16]=1[O:23][CH3:24])([O-])=O>CN(C=O)C>[N:1]1([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[C:16]=2[O:23][CH3:24])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1c([N+](=O)[O-])ccnc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(-n2ccnc2)ccnc1C#N
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of 0.2 g (0.51 mmol) 2-{N-meta-[4-(trifluoromethylphenoxy)phenyl]} aminocarbonyl-3-hydroxy-4-amino pyridine (prepared according to the method described in WO 0149666) and 78 mg (0.56 mmol) of 2,5-dimethoxytetrahydrofuran) in 1 ml of glacial acetic acid, is heated at 110° C. for 1 hour. The reaction is cooled and solvent evaporated, the residue is dissolved in dichloromethane and washed with aqueous sodium bicarbonate, the organic phase was dried over MgSO4 and solvent evaporated. The crude product was chromatographed on silica to yield 137 mg (61% yield) of a yellow solid. (M+1=440) 2-N-(3-trifluoromethyl phenyl) aminocarbonyl-3-hydroxy-4-(imidazol-1-yl) pyridine (compound 2-24) A mixture of 1.36 g (20 mmol) of imidazol and 60.52 g (20 mmol) of cesium carbonate is stirred at room temperature in 20 ml of DMF for 20 minutes. 3.58 g (20 mmol) of 4-nitro-3-methoxy-2-cyano pyridine (prepared according to the methods described in WO 0149667) is added in one pot and the mixture is stirred overnight. DMF is removed in vacuo and the residue is partitioned between water and ethyl acetate. The aqueous phase is further extracted with ethyl acetate. The organic phases are washed with dilute brine, dried and solvent evaporated. Purification on silica gave 1.4 g of 4-(imidazol-1-yl)-3-methoxy-2-cyano pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:12][CH3:13])=[C:4]([OH:11])[C:5]([S:9][CH3:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:14][S:15]C1C=C(SC)C=CC=1O>>[CH3:1][C:2]1[C:3]([S:12][CH3:13])=[C:4]([OH:11])[C:5]([S:9][CH3:10])=[C:6]([CH3:8])[C:7]=1[S:15][CH3:14]
Reactant: CSc1ccc(O)c(SC)c1
Reactant: CSc1c(C)cc(C)c(SC)c1O
Product: CSc1c(C)c(SC)c(O)c(SC)c1C

Procedure:
NMR shows fraction 2 to be a mixture of about 90:10 of 3,5-dimethyl-2,6-bis(methylthio)phenol and 2,4-bis(methylthio)phenol.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:12]=[C:13]([C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=2)[N:14]=[N:15][C:16]=1[O:17][CH3:18].O.C([O:33][C:34]1[N:39]=[C:38]([O:40]C(C)(C)C)[C:37](B(O)O)=[CH:36][N:35]=1)(C)(C)C>>[OH:26][C:22]1[C:23]([CH3:25])=[CH:24][C:19]([C:13]2[N:14]=[N:15][C:16]([O:17][CH3:18])=[C:11]([C:3]3[NH:4][C:5]4[C:10]([C:2]=3[C:37]3[C:38](=[O:40])[NH:39][C:34](=[O:33])[NH:35][CH:36]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:12]=2)=[CH:20][C:21]=1[CH3:27]
Reactant: CC(C)(C)Oc1ncc(B(O)O)c(OC(C)(C)C)n1
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2ccccc2c1Br
Solvent: O
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2ccccc2c1-c1c[nH]c(=O)[nH]c1=O

Procedure:
111 mg of 4-[5-(3-bromo-1H-indol-2-yl)-6-methoxy-pyridazin-3-yl]-2,6-dimethyl-phenol is treated analogously to example 6 (c), using 2,4-di(tert-butoxy)pyrimidin-5-yl boronic acid hydrate. Yield 100 mg. LC-MS (ES+) 455 (M+H)+.
Reaction SMILES: [C:1]1(=[O:14])[N:12]2[C:13]3[C:9]([CH:10]=[CH:11]2)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][NH:3][CH2:2]1.[OH-].[K+].[I:17]I>CN(C=O)C>[I:17][C:8]1[CH:7]=[CH:6][C:5]2[CH2:4][NH:3][CH2:2][C:1](=[O:14])[N:12]3[C:13]=2[C:9]=1[CH:10]=[CH:11]3
Reactant: O=C1CNCc2cccc3ccn1c23
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C1CNCc2ccc(I)c3ccn1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a pale-yellow solution of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 42, 0.051 g, 0.274 mmol) in 5 mL DMF was added KOH (0.058 g, 1.03 mmol) and iodine (0.139 g, 0.548 mmol) at rt. The reaction mixture was stirred at rt overnight, at which time solvent was removed in vacuo. The residue was taken up in EtOAc and washed with 0.1% aq sodium bisulfite, H2O and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 0.078 g (92%) of a pale-yellow solid: 1H NMR (DMSO-d6) δ 3.56-3.59 (m, 2H), 4.40 (m, 2H), 7.26 (t, 1H, J=7.5 Hz), 7.52 (d, 1H, J=7.5 Hz), 7.67 (s, 1H), 7.93 (d, 1H, J=7.5 Hz), 8.37 (t, 1H, J=5.3 Hz). HRMS calcd. for C11H9N2OI (M+) 311.9761, found 311.9776. Anal. (C11H9N2OI) C, H, N.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CS([Cl:30])(=O)=O>C(Cl)Cl>[Cl:30][CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(c1cccc(CO)n1)N1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cccc(CCl)n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 530 mg of (6-hydroxymethylpyridin-2-yl)morpholin-4-ylmethanone and 614 mg of diisopropylethyl-amine in 10 mL of methylene chloride at ice temperature, 0.28 mL of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (methylene chloride-ethanol=50:1) to give 570 mg of (6-chloromethylpyridin-2-yl)morpholin-4-ylmethanone as a yellow oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([CH:5]1[O:7][CH2:6]1)Cl.[OH:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][OH:14]>O1CCOCC1>[O:7]1[CH:5]([CH2:3][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][CH2:13][OH:14])[CH2:6]1
Reactant: ClCC1CO1
Reactant: OCCOc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: OCCOc1ccccc1OCC1CO1
Temperature: 50 °C
Yield: 41.7 %

Procedure:
69 ml of 1 N sodium hydroxide and 7.3 ml of epichlorohydrin were added to a solution of 7.2 g of 2-(2-hydroxyphenoxy)ethanol in 50 ml of dioxane, and the mixture was heated at 50° C. for 2 hours with stirring. The reaction solution was extracted with chloroform, washed with water and dried. The solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column to afford 4.1 g (yield 41.7%) of 1,2-epoxy-3-[2-(2-hydroxyethoxy)phenoxy]propane as a colorless oil.
Reaction SMILES: [Br:1]Br.[N+:3]([CH:6]=[C:7]1[NH:12][CH2:11][CH2:10][CH2:9][S:8]1)([O-:5])=[O:4]>C(Cl)Cl.O>[Br:1][C:6]([N+:3]([O-:5])=[O:4])=[C:7]1[NH:12][CH2:11][CH2:10][CH2:9][S:8]1
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])C(Br)=C1NCCCS1

Procedure:
A solution of 3.2 g of bromine in 10 ml of methylene chloride was added dropwise to a solution of 3.2 g of 1A in 50 ml of water, the temperature being held at 5°-10°. The mixture was then stirred for 45 minutes when 200 ml of methylene chloride was added to dissolve the solid material. The organic phase was separated, washed with water, dried (Na2SO4) and concentrated under reduced pressure to give a yellow solid. This was washed with ether to give 2A as a yellow solid, m.p. 122° (with decomposition).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:10])=[O:9]
Reactant: C1COCCN1
Reactant: CNS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of 4-fluoro-N-methyl-3-nitrobenzenesulfonamide (2.00 g, 8.54 mmol) and morpholine (0.744 g, 8.54 mmol) in THF (100 mL), was added N,N-diisopropylethylamine (2.21 g, 17.08 mmol). The resulting solution was stirred at 50° C. overnight. In the morning, the reaction mixture was cooled to room temperature and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to obtain N-methyl-4-(4-morpholinyl)-3-nitrobenzenesulfonamide (2.5 g, 97%) as a red oil. MS (m/z) 302.0 (M+H+)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:12]1[N:17]=[C:16]([Cl:18])[CH:15]=[C:14]([O:19][CH3:20])[N:13]=1.[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22]>C1COCC1>[CH2:25]([O:24][C:21](=[O:23])[CH2:22][C:12]1[N:17]=[C:16]([Cl:18])[CH:15]=[C:14]([O:19][CH3:20])[N:13]=1)[CH3:26]
Reactant: COc1cc(Cl)nc(Cl)n1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nc(Cl)cc(OC)n1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
91.4 ml of 1M lithium bis(trimethylsilyl)amide (THF) are added dropwise to a solution of 7.4 g of 2,4-dichloro-6-methoxypyrimidine and 4.5 ml of ethyl acetate in 100 ml of anhydrous THF cooled to −75° C. in a dry ice/acetone bath. The reaction medium is stirred at −75° C. for one hour. The cooling bath is removed so as to allow the temperature to rise to 22° C. The reaction medium is stirred at 22° C. for one hour. 100 ml of water and 400 ml of ethyl acetate are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure so as to give 9.5 g of (4-chloro-6-methoxypyrimidin-2-yl)acetic acid ethyl ester in the form of an orange oil, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13](=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[NH2:21][C:17]1[CH:16]=[C:15]([CH2:14][C:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[O:24])[CH:20]=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc(N)c1
Yield: 101.1 %

Procedure:
A suspension of platinum oxide (0.35 g) in ethyl acetate (100 ml) containing methyl 4-chloro-2-(3-nitrophenyl)acetamidobenzoate (9.96 g, 28.6 mmol) was shaken under an atmosphere of hydrogen at 40 psi until hydrogen uptake had ceased. The suspension was filtered and the filtrate evaporated to leave methyl 2-(3-aminophenyl)acetamido-4-chlorobenzoate as a pale green solid (9.22 g); δ(CDCl3) 3.65 (2H, s, CH2), 3.66 (3H, s, OCH3), 6.61 (1H, dd, J 7.9 and 2.1 Hz, ArH), 6.70 (1H, s, ArH), 6.74 (1H, d, J 7.6 Hz, ArH), 7.01 (1H, dd, J 8.6 and 2.0 Hz, 5-H), 7.14 (1H, d, J 7.7 Hz, ArH), 7.89 (1H, d, J 8.6 Hz, 6-H), 8.81 (1H, d, J 2.0 Hz, 3-H) and 11.03 (1H, br s, CONH).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH:38]([S:41](Cl)(=[O:43])=[O:42])([CH3:40])[CH3:39]>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:41]([CH:38]([CH3:40])[CH3:39])(=[O:43])=[O:42])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of the product of Example 353E (16.2 mg, 0.036 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and isopropyl sulfonyl chloride was added (0.0043 mL, 0.038 mmol). The mixture was warmed to 23° C. and stirred for 3 hours. Additional isopropyl sulfonyl chloride (0.006 mL, 0.055 mmol) was added and the reaction mixture was stirred at 23° C. for 15 hours. The reaction mixture was stirred at 50° C. for 2 hours. Additional triethylamine (0.040 mL, 0.287 mmol) and isopropyl sulfonyl chloride (0.010 mL, 0.091 mmol) were added and the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (6.7 mg, 33%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 0.21 (bs, 2 H) 0.48 (d, 2 H) 0.98 (m, 1 H) 1.24 (d, J=6.99 Hz, 6 H) 3.19 (m, 1 H) 4.25 (s, 2 H) 5.85 (t, 1 H) 6.76 (s, 1 H) 6.92 (t, 1 H) 7.34 (m, 2 H) 7.57 (d, 1 H) 7.96 (d, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]I>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:25])[C:18]=2[Cl:24])[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Cl)cc2Cl)on1
Reactant: CI
Product: Cc1c(Cl)ccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)c1Cl
Yield: 45 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-dichlorophenyl)isoxazole (0.3 g) and methyl iodide (0.08 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.14 g, 45%) as a colorless powder.