Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[O-]CC.[Na+].[CH3:21][O:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25]>C(O)C>[CH3:21][O:22][C:23](=[O:27])[CH:24]([CH3:26])[CH2:25][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: C=C(C)C(=O)OC
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C(C)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 94.5 %

Procedure:
1-(4-Trifluoromethyl-phenyl)-piperazine (460 mg; 2.0 mmol) and sodium ethoxide (150 mg; 2.21 mmol) are dissolved in ethanol (2 mL) and irradiated for 5 minutes in a mono-mode microwave oven at 60° C. 2-Methyl-acrylic acid methyl ester (400 μL; 4.0 mmol) is then added and the resulting mixture is irradiated for 50 minutes in a mono-mode microwave oven at 100° C. The reaction is concentrated under reduced pressure, diluted in ethylacetate (10 mL) and extracted with water (2×5 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product (623 mg; 1.89 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH:30]2[CH2:32][O:31]2)=[CH:26][CH:25]=1>>[OH:31][CH:30]([CH2:29][O:28][C:27]1[CH:33]=[CH:34][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[CH2:32][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: COc1ccc(OCC2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: COc1ccc(OCC(O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 175 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(4-methoxyphenoxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 482 [M+H]; Rt=0.99 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH3:10][S:11][Na]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:11][CH3:10])[CH:3]=1
Reactant: CS[Na]
Reactant: BrCc1cc(Br)ccn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCc1cc(Br)ccn1
Reaction time: 0.17 h
Yield: 12.6 %

Procedure:
Crude 4-bromo-2-(bromomethyl)pyridine was dissolved in N,N-dimethylformamide (3.000 mL), and mixture was cooled on an ice bath followed by the portion wise addition of methylsulfanylsodium (2.037 g, 29.07 mmol). Reaction mixture was left to stir for 10 minutes. The mixture was diluted with ethyl acetate, organic layer was washed with water and brine. Organic layer was extracted, dried over MgSO4 and concentrated in vacuo to a solid. Residue was purification by silica gel column chromatography loaded with dichloromethane and eluted with 50% diethylether/petroleum ether. Product fractions were combined and concentrated in vacuo to give the sub-titled product (0.8 g, 12.6%). 1H NMR (400.0 MHz, DMSO-d6) δ 2.25 (s, 3H), 3.80 (s, 2H), 7.4 (d, 1H), 7.6 (s, 1H), 8.4 (d, 1H); LC/MS m/z 220.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7]2.[NH2:14][CH2:15][CH2:16][N:17]1[CH:22]=[C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][C:18]1=[O:28]>CC(O)C>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:14][CH2:15][CH2:16][N:17]3[CH:22]=[C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:20]=[CH:19][C:18]3=[O:28])=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: NCCn1cc(-c2cccs2)ccc1=O
Solvent: CC(C)O
Product: COc1cnc2c(NCCn3cc(-c4cccs4)ccc3=O)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 8-chloro-3-methoxy-1,5-naphthyridine (35 mg, 182 μmol) and 1-(2-aminoethyl)-5-(thiophen-2-yl)pyridin-2(1H)-one (40 mg, 182 μmol) in iPrOH (0.5 mL) was heated to 100° C. overnight. The mixture was partitioned between CH2Cl2 (10 mL) and 1M NaOH (5 mL). The aqueous was further extracted with CH2Cl2 (2×5 mL) and combined organics dried over MgSO4 then purified on silica (12 g) eluting with 15-60% of 5% (MeOH/CH2Cl2). MS (ESI pos. ion) m/z (MH+): 379. Calc'd exact mass for C20H18N4O2S: 378. 1H NMR (400 MHz, Chloroform-d) 8 ppm 3.09 (br. s., 1H) 3.85 (q, J=6.13 Hz, 2H) 3.93 (s, 3H) 4.28 (t, J=5.97 Hz, 2H) 6.57 (d, J=5.48 Hz, 1H) 6.65 (d, J=9.59 Hz, 1H) 6.81 (d, J=2.74 Hz, 1H) 6.91-7.00 (m, 2H) 7.10-7.15 (m, 1H) 7.34 (d, J=2.54 Hz, 1H) 7.50-7.58 (m, 2H) 8.40 (d, J=2.74 Hz, 1H) 8.45 (d, J=5.48 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:41]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[CH:43]=1)[CH2:19][N:20]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[S:21]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:25]=1[OH:32])(=[O:23])=[O:22].CCN(CC)CC>C(Cl)Cl>[Cl:31][C:26]1[C:25]([OH:32])=[C:24]([S:21]([N:20]([CH2:19][C:18]2[CH:41]=[C:42]([O:44][C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[CH:43]=[C:16]([CH2:15][NH:14][S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=3[OH:13])(=[O:10])=[O:11])[CH:17]=2)[CH2:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)(=[O:23])=[O:22])[CH:29]=[C:28]([Cl:30])[CH:27]=1
Reactant: NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1)c1cc(Cl)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.9 %

Procedure:
To a solution of 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (27.1 mg, 0.104 mmol) in 4 mL of CH2Cl2 was added solid N-(3-(aminomethyl)-5-(4-fluorophenoxy)benzyl)-3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzenesulfonamide (60 mg, 0.104 mmol) followed by Et3N (110 μL) at rt. The mixture was stirred at rt for 45 min. Direct purification of the reaction mixture by prep HPLC provided the desired product (71 mg, 85%). 1H NMR (CD3OD): δ 7.68 (s, 1H), 7.60 (s, 1H), 7.49 (s, 2H), 7.13˜6.90 (m, 8H), 6.67 (s, 1H), 6.61 (s, 1H), 6.45 (s, 1H), 4.44 (s, 2H), 4.30 (s, 2H), 4.08 (s, 2H); MS (ESI): (M+H)+=805.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[N+:8]([C:6]1[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=[C:2]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[CH:7]=1)([O-:10])=[O:9]
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(-n2ccccc2=O)cc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 95 %

Procedure:
To a solution of N-(3-bromo-5-nitrophenyl)acetamide (1 g, 3.85 mmol), pyridin-2-ol (0.4 g, 4.24 mmol, 1.1 eq.), potassium carbonate (1 g, 1.3 mmol, 1.0 eq.) and copper(I) iodide (10 mg) in toluene (20 ml) was added trans cyclohexyl diamine (5 mg, 0.039 mmol, 0.01 eq.) and the mixture was heated at 100° C. for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the product in 95% yield (1 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]([CH2:14][C:15]([CH3:17])=[CH2:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[S:21]>CN(C)C=O>[CH3:18][N:19]([C:20](=[S:21])[O:3][C:4]1[C:13]([CH2:14][C:15]([CH3:17])=[CH2:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:23]
Reactant: CN(C)C(=S)Cl
Reactant: C=C(C)Cc1cccc(C(=O)OC)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)Cc1cccc(C(=O)OC)c1OC(=S)N(C)C
Yield: 60.1 %

Procedure:
To 1 liter of dry dimethylformamide were added 16 g of 60% sodium hydride in oil. After stirring under a nitrogen atmosphere, 81.7 g of 2-hydroxy-3-(2-methyl-2-propenyl) benzoic acid, methyl ester, as a solution in dimethylformamide, were added in dropwise fashion. After stirring at room temperature, a solution 49.6 g of dimethylthiocarbamoyl chloride in dimethylformamide was added over a one hour period. The reaction mixture was stirred at room temperature overnight, then poured onto ice and extracted with diethyl ether and ethyl acetate. The combined organic extracts were washed successively with a 10% sodium hydroxide solution and water, dried over sodium sulfate, and concentrated in vacuo. The residue was vacuum distilled, and the fraction distilling at 162°-168° C. and 0.6 torr provided 69.9 g of the desired subtitle intermediate. NMR, MS.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH2:34][OH:35])([CH2:32][OH:33])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([C:28]([F:31])([F:30])[F:29])[CH:12]=1)(C)(C)C.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:37].[NH2:7][C:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([C:28]([F:29])([F:30])[F:31])[CH:12]=1)([CH2:32][OH:33])[CH2:34][OH:35]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCc2ccccc2)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(CO)(CO)CCc1ccc(OCCCCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound 4-1 (490 mg) was dissolved in methylene chloride (7 ml), hydrogen chloride-containing dioxane (4 mol/l, 5 ml) was added, and the mixture was stirred at room temperature for 12 hr stirred for. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (370 mg) as a white powder.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[CH3:10][N:11]1[C:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:14]=2[CH:13]=[N:12]1.[CH:29]([S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][C:36]=1[CH3:44])(=[O:34])=[O:33])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:29]([S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([N:26]2[CH2:27][CH2:28][C:23]3([C:14]4[CH:13]=[N:12][N:11]([CH3:10])[C:15]=4[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[O:22]3)[CH2:24][CH2:25]2)=[O:40])=[CH:37][C:36]=1[CH3:44])(=[O:34])=[O:33])([CH3:31])[CH3:30]
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Reactant: Cc1cc(C(=O)O)ccc1S(=O)(=O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1S(=O)(=O)C(C)C
Temperature: 40 °C
Yield: 67.6 %

Procedure:
Triethylamine (152 μL, 1.1 mmol) was added to a mixture of 1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] dihydrochloride (108 mg, 0.33 mmol), 4-(isopropylsulfonyl)-3-methylbenzoic acid (80 mg, 0.33 mmol), HATU (126 mg, 0.33 mmol), and dichloromethane (2 mL) at 25° C. The mixture was heated at 40° C. for 3 h. The mixture was concentrated and the residue was purified by column chromatography (0-100% ethyl acetate/hexanes) to give (4-(isopropylsulfonyl)-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (107 mg, 65%) as a fluffy white solid. ESI-MS m/z calc. 479.6, found 480.3 (M+1)+. Retention time: 2.24 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][O:14][CH3:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCBr
Reactant: COc1ccc(Br)c(O)c1
Product: COCCOc1cc(OC)ccc1Br

Procedure:
Starting from commercially available 2-bromo-5-methoxy-phenol and 1-bromo-2-methoxy-ethane the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:13]O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]1([CH2:13][Br:34])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCC1(COCc2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC1(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
58.9 g of 1-benzyloxymethyl-1-(hydroxymethyl)cyclopropane and 88.5 g of triphenylphosphine are dissolved in 600 ml of methylene chloride, and 60 g of N-bromosuccinimide are added in portions at 0° C. The reaction mixture is stirred at room temperature for 16 h and concentrated and the residue is purified by means of FC over 3 kg of silica gel with a 1:1 mixture of methylene chloride and hexane as the eluting agent. This gives 68 g of the pure title compound: Rf (1:1 mixture from methylene chloride and hexane)=0.50.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:15])=[O:12])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(CC(=O)O)cc1
Product: CSc1ccc(CC(=O)Cl)cc1
Temperature: 90 °C
Yield: 68.7 %

Procedure:
A mixture of 158 g (0.87 mole) of 4-methylthiophenylacetic acid and 150 ml (2 moles) of thionyl chloride was heated at 90° C. for 2 hours. After completion of the reaction, an excess of thionyl chloride was distilled off under reduced pressure, giving about 120 g of 4-methylthiophenylacetyl chloride as a black oily product. The oily product thus obtained was subjected to the subsequent reaction without isolation and purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][NH2:41]>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([NH:41][CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][CH2:29][NH2:28])=[O:9]
Reactant: O=C(O)C=Cc1cccc(O)c1
Reactant: NCCCNCCCCNCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: NCCCNCCCCNCCCNC(=O)C=Cc1cccc(O)c1
Reaction time: 21 h
Yield: 26.6 %

Procedure:
According to the General Procedure using 3-hydroxycinnamic acid (160 mg, 0.97 mMol), dicyclohexylcarbodiimide (226 mg, 1.10 mMol), and spermine (400 mg, 1.98 mMol) in dichloromethane (6 ml), activation during 2 h and coupling over 21 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 15-22 and was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH, 4:2:1), Rf =0.22, (108 mg, 32%), lyophilisation gave 90 mg of a yellow viscous gum whose spectroscopic data include: UVmax 213 (emax 3 500), 230sh and 375 (emax 3 800) nm; pmr (90 MHz, 2H2O) 1.4-2.0 (m, 8H, 4×CH2 --CH2), 2.6-3.0 (m, 10H, 5×CH2 --N), 3.35 (t, J=7, 2H, CON2H--CH2 --CH2), 6.4 (d, J=16, 1H, CH=CH--CO), 3.55 (s, 2H, Ar--CH2 --CO), 6.6-6.9 (m, 3H, 3×ArH 2,4,6), and 7.2-7.6 (m, 2H, ArH 5 and ArCH=CH)ppm; M+1 349 (FAB matrix m-nitrobenzyl alcohol) C19H32N4O2 requires M+ 348).
Reaction SMILES: I.[CH3:2][N:3]([CH2:8][CH2:9][S:10][CH3:11])[CH:4](SC)[CH3:5].[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][C@@H:18]([OH:39])[C@@H:19]2[NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])=[CH:27][C:26]=2[F:38])=[O:24])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:11][S:10][CH2:9][CH2:8][N:3]([CH3:2])[C:4](=[N:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][C@@H:18]([OH:39])[C@@H:19]2[NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])=[CH:27][C:26]=2[F:38])=[O:24])=[CH:15][CH:14]=1)[CH3:5]
Reactant: CSCCN(C)C(C)SC
Reactant: Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3F)cc1F)[C@H](O)C2
Agent: I
Solvent: c1ccncc1
Product: CSCCN(C)C(C)=Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3F)cc1F)[C@H](O)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 22.5 %

Procedure:
Dissolve the crude HI salt of methyl-(2-methylsulfanylethyl)(1-methylsulfanylethyl)amine (90.1 mg, 0.295 mmol) and 3,2′-difluorobiphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide (101.3 mg, 0.266 mmol) in 10 mL pyridine. Allow the reaction to stir at 25° C. for 21 hours. Remove the solvent in vacuo and partition the residue between methylene chloride and saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to give 91.5 mg of crude product. Purify via silica gel column chromatography (2% MeOH/CHCl3 to 5% MeOH/CHCl3) to afford 30.5 mg of the titled product (22% yield). MS (ES): m/z 510.1(M+H).
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[NH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C)C=O>[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:11]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:26])([CH3:25])[CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1nc2cccc(CO)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(C)cccc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The stirred solution of 1.60 g of methyl 7-hydroxymethyl-1H-benzoimidazole-2-carboxylate and 13.0 ml of N,N-dimethylformamide is admixed at 0° C. with 0.274 g of sodium hydride dispersion (55%) and, after 60 minutes, with 1.33 ml of 2-(trimethylsilyl)ethoxymethyl chloride. The mixture is stirred at room temperature over 3 hours, subsequently poured onto ice-water (100 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed successively with water (100 ml) and brine (100 ml), dried over sodium sulphate and concentrated. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (1:2 EtOAc-heptane); Rt=5.16; m.p. 59.6-59.8° C.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Li+].[CH2:23](I)[CH2:24][CH3:25]>>[C:1]([C:3]1[CH:20]=[CH:19][C:6]([N:7]=[C:8]2[N:13]([CH2:23][CH2:24][CH3:25])[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[S:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCI
Reactant: N#Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc(C#N)cc2)sc2ncccc2c1=O
Yield: 70.9 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.21 mmol) of 2-(4-cyanoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 42 mg of lithium hydride and 655 mg of propyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 734 mg of 2-[(4-cyanophenyl)imino]-2,3-dihydro-3-propyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (71%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 100 mg of 2-[N- (4-cyanophenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (10%, recrystallized from ether) as a high polarity substance.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11].[OH:32]O>CC(O)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7]([CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])=[O:32]
Reactant: O=C(CCSCc1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: OO
Solvent: CC(=O)O
Product: O=C(CCS(=O)Cc1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 1 h

Procedure:
To a stirring solution of 0.69 g (1.5 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylmethyl)thio]-1-oxopropyl]hydrazide (13), prepared as described above in Example 13, in 5 mL of HOAc was added 0.13 mL (1.5 mmol) of a 30% hydrogen peroxide solution. After one hour, the reaction mixture was lyophilized. The product was recrystallized from EtOAc-hexanes. The yield of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylmethyl)sulfinyl]-1-oxopropyl]hydrazide (60) was 0.56 g (79%). Analysis calculated for C22H20N3O5SCl (M.W. 473.93): C, 55.76; H, 4.25; N, 8.87; Cl, 7.48; S, 6.77. Found: C, 55.67; H, 4.30; N, 8.79; Cl, 7.47; S, 6.56.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]>>[CH3:14][O:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][CH2:7][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:19][C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Reactant: CC(C)(C)NCCC1CCCCC1
Product: COC(=O)c1ccc(CN(CCC2CCCCC2)C(C)(C)C)cc1-c1ccccc1C

Procedure:
The desired compound was prepared using the method described in Example 1178G starting with N-t-butyl-N-(2-cyclohexylethyl)amine, prepared as in Example 1181A, and 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1178A-D. m/e (ESI) 422 (MH+)
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:12]1[CH2:21][CH2:20][CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[N:12]1[CH2:21][CH2:20][CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13]1
Reactant: COC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(c2c(F)cccc2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
A mixture of difluoronitrobenzene (0.34 mL, 3.10 mmol), methyl isonipecotate (0.51 mL, 3.78 mmol), and diisopropylethylamine (1.08 mL, 6.20 mmol) in acetonitrile (15 mL) was heated at 80° C. overnight. The solvents were removed in vacuo. Chromatographic purification (20% ethyl acetate:hexane) of the residue gave Int-20a (0.85 g, 97%) as a yellow oil.
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[N:14]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Cl:12][C:13]1[N:14]=[C:15]([C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CC1(C)OB(c2cccc(Cl)n2)OC1(C)C
Reactant: COC(=O)c1cccnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccnc1-c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.49 g (0.70 mmol) of (Ph3P)2PdCl2 is added under argan to a solution of 3.0 g (13.9 mmol) of methyl 2-bromonicotinate in 10 ml of dioxane and the mixture is stirred for 30 min at room temperature. Thereafter, 3.33 g (13.78 mmol) of 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 5.76 g (41.68 mmol) of K2CO3 and 11 ml of H2O are added in succession to the mixture, and the mixture is stirred for 6 hours under reflux and subsequently allowed to stand overnight at room temperature (RT). For work-up, the reaction mixture is poured into 150 ml of H2O and extracted repeatedly with CH2Cl2. The combined organic phases are dried over Na2SO4 and subsequently concentrated. The crude product thus obtained is purified by chromatography on silica gel using heptane/ethyl acetate (7:3) as the mobile phase. This gives 2.50 g (72%) of product as a colorless oil; 1H NMR (CDCl3) δ 8.70 (dd, 1H), 8.15 (dd, 1H), 7.95 (dd, 1H), 7.80 (dd, 1H), 7.40 (dd, 1H), 7.37 (dd, 1H), 3.90 (s, 3H, COOMe).