Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:36]=[CH:35][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[CH:22]=2)=[CH:18][C:17]=1[F:37]>C(#N)C.C(OCC)C>[F:37][C:17]1[CH:18]=[C:19]([CH:35]=[CH:36][C:16]=1[NH:15][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:11])[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cc1F
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cc1F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 12.8 %

Procedure:
To a solution of 2-phenylacetyl chloride (0.054 ml, 0.43 mmol) in acetonitrile (4.3 ml) was added potassium thiocyanate (83 mg) at room temperature, followed by stirring under a nitrogen atmosphere at 60° C. for 1.5 hrs. The reaction mixture was cooled in an ice bath, and then a solution of pyrrolidine-1-carboxylic acid [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]amide (90 mg) in acetonitrile (4.0 ml) was added thereto, followed by warming the reaction mixture to room temperature and stirring for 3 hrs. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:2, then ethyl acetate). Fractions containing the target compound were concentrated to give a solid, which was suspended in diethyl ether. The solid was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (18 mg, 13%) as colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]([O:15]CC)=[CH2:14])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>C1COCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13](=[O:14])[CH2:15][Br:18])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1cc(=O)oc2cc(Br)ccc12
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CBr)c1cc(=O)oc2cc(Br)ccc12
Reaction time: 0.5 h

Procedure:
To a solution of 7-bromo-4-(1-ethoxyvinyl)-2H-chromen-2-one (2.0 g, 6.8 mmol) in THF and H2O is added N-bromosuccinimide (1.3 g, 14.2 mmol) with stirring for 30 min. Toluene is added and the solvent is evaporated. The residue is chromatographed on silica gel (hexane/EtOAc; 80:20) to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([O:17][CH3:18])[CH:4]=1)=[O:2].[N+:19]([O-])([OH:21])=[O:20].O.[K+].[Br-]>C(Cl)Cl>[CH:1]([C:3]1[C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([O:17][CH3:18])[CH:4]=1)=[O:2]
Reactant: COC(=O)CCCOc1ccc(C=O)cc1OC
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a pale pink solution of methyl 4-(4′-formyl-2′-methoxyphenoxy)butanoate (4) (3 g, 12.3 mmol) in DCM (20 cm3) was added dropwise, at 0° C. fuming nitric acid (1.5 cm3, 37.0 mmol). The resulting green solution was stirred at 00° C. for a further 30 mins before being allowed to spontaneously warm to r.t., where it remained for 3 hours. The subsequent bright yellow suspension was poured onto iced water (50 cm3) and extracted with DCM (3×30 cm3). The combined organic phase was washed with sat. NaHCO3 solution (2×50 cm3), followed by water (2×50 cm3) before being dried and concentrated in vacuo providing a bright yellow solid. The desired compound 5 was used without further purification (2.48 g, 68%). A small amount of material (250 mg, 0.84 mmol) was purified via column chromatography (SiO2, CH2Cl2) so that complete characterisation data could be obtained, m.p. 75° C. [lit. (D. L. McMinn and M. M. Greenberg, Tetrahedron, 1996, 52, 3827.) m.p. 76-78° C.]. Found C, 52.7; H, 5.2; N, 4.8; C13H15NO7 requires C, 52.5; H, 5.1; N, 4.7%; Rf 0.44 (SiO2, CH2Cl2); νmax (KBr disc)/cm−1 3100-2700 (m), 1735 (s), 1690 (s), 1290, 1220; 6, (200 MHz, CDCl3) 2.23 (2H, q, J=7.1 Hz, CH2), 2.57 (2H, t, J=7.1 Hz, CH2), 3.71 (3H, s, OCH3), 3.99 (3H, s, OCH3), 4.21 (2H, t, J=7.1 Hz, CH2), 7.40 (1H, s, H-3′), 7.61 (1H, s, H-6′), 10.44 (1H, s, CHO) ppm; δC (100 MHz, CDCl3) 24.1 (CH2), 30.2 (CH2), 51.8 (OCH3), 56.6 (OCH3), 59.6 (CH2), 108.1 (CH), 109.9 (CH), 125.5, 143.8, 151.7, 153.4, 173.2 (COOCH3), 187.8 (CHO) ppm; m/z (FAB) 298 [(MH+), 40%].
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([CH2:21][CH2:22][NH:23][C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:20])[C:16](C)(C)C)(=[O:6])[C:2](C)(C)C.[CH3:32][I:33]>CO>[I-:33].[CH3:32][N+:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:10]2[CH:11]=[CH:12][C:13]([O:14][C:15](=[O:20])[CH3:16])=[C:8]([O:7][C:1](=[O:6])[CH3:2])[CH:9]=2)[CH:27]=1
Reactant: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1OC(=O)C(C)(C)C
Reactant: CI
Solvent: CO
Product: CC(=O)Oc1ccc(CCNC(=O)c2ccc[n+](C)c2)cc1OC(C)=O
Product: [I-]

Procedure:
To a solution of 1.71 g (5 mmol) of 3-{N-[β-(3,4-diacetoxyphenyl)ethyl]}carbamoylpyridine (prepared like compound 8c), 1.41 g (10 mmol) of methyl iodide were added and the mixture was refluxed overnight under stirring. The acetone solution was then decanted from the insoluble oily residue. Ether was added to the acetone solution and the solid which separated was crystallized from acetone/ether. Yield, 1.9 g (78%) of yellow crystalline needles, m.p. 171°-173° C. U.V. (methanol) 215, 265 nm; NMR (D2O) δ 8.86-7.63 (ms, 4H, C5H4N+), 6.66 (bs, 3H, C6H3), 4.4 (s, 3H, --N+ --CH3), 3.50 (t, 2H, --N--CH2), 3.03 (t, 2H, CH2), 2.21 (bs, 6H, 2 COCH3). Anal. Calcd for C19H21IN2O5 : C, 47.12; H, 4.37; N, 5.78. Found: C, 47.23; H, 4.38; N, 5.78.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][C:36](=[O:39])[N:35]5COCC[Si](C)(C)C)=[CH:30][CH:29]=4)=[C:14]([CH2:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.CCOCC.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54].C(Cl)Cl>>[F:56][C:55]([F:58])([F:57])[C:53]([OH:59])=[O:54].[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([N:34]5[CH:38]=[N:37][C:36](=[O:39])[NH:35]5)=[CH:32][CH:33]=4)=[C:14]([CH2:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1c(=O)ncn1-c1ccc(-c2c(CCc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1ncn(-c2ccc(-c3c(CCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cc2)[nH]1

Procedure:
A solution of compound 52e (45 mg, 0.070 mmol) in TFA:DCM (1:3 v/v, 5 mL) was stirred overnight at rt. The resulting mixture was concentrated under reduced pressure and the residue obtained was treated with Et2O (10 mL). The solids formed were collected by filtration and washed with Et2O (2×20 mL). The title compound 59 was obtained as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.92 (d, J=8.4 Hz, 1H), 8.87 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.06-8.03 (m, 3H), 7.94-7.85 (m, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 6.30 (d, J=5.7 Hz, 1H), 3.56-3.43 (m, 12H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C29H26N8O2: 519.2 (M+H). Found: 519.1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][O:25][CH3:26]>C(O)CCC>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH2:23][CH2:24][O:25][CH3:26])[C:2]1[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=1
Reactant: COCCNCCOC
Reactant: Nc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(CCOC)c1cc(N)ncn1
Temperature: 180 °C
Reaction time: 24 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.3 g, 2.32 mmol) and diisopropylethylamine (0.30 g, 2.32 mmol) were suspended in n-butanol and then 2-methoxy-N-(2-methoxyethyl)ethanamine 6-1 (0.31 g, 2.32 mmol) was added. The reaction was stirred at 180° C. for 24 hours. The solvent was removed under reduced pressure and the product 6-2 was purified on a silica column. 1H-NMR (DMSO): 7.91 ppm (s, 1H); 6.10 ppm (2H); 5.51 ppm (s, 1H); 3.45 ppm (m, 4H); 3.45 ppm (m, 4H); 3.25 ppm (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(c2ccc(N)cc2)CC1

Procedure:
A mixture of intermediate (3) (0.0055 mol) in THF (50 ml) was hydrogenated with palladium on carbon (10%; 0.16 g) as a catalyst for 30 minutes at a temperature of 50° C. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, yielding [1-(4-amino-phenyl)-piperidin-4-yl]-acetic acid ethyl ester (intermediate 4).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[I-].[Na+].Br.BrC[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>CN(C=O)C>[CH3:25][O:24][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6]([C:5]3[CH:26]=[CH:27][N:28]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[C:3](=[O:2])[CH:4]=3)=[O:7])[S:10][C:11]=2[C:17]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:16][CH:15]=1
Reactant: COc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Reactant: BrCCc1ccccn1
Agent: Br
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccn(Cc4ccccn4)c(=O)c3)nc12

Procedure:
From 2-methoxy-N-(4-methoxy-7-morpholin-4-yl -benzothiazol-2-yl)-isonicotinamide with sodium iodide and 2-(bromoethyl)pyridine hydrobromide in DMF. ES-MS m/e (%): 500 (M+Na+, 30), 478 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.N[CH:22]1[CH2:25][CH2:24][CH:23]1[OH:26].C[N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:28][CH:25]3[CH2:24][CH:23]([OH:26])[CH2:22]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1CCC1O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NC4CC(O)C4)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 14 (90 mg, 0.34 mmol) was reacted with 2-aminocyclobutanol (CAS 4640-44-2) (59 mg, 0.68 mmol), HATU (145 mg, 0.38 mmol) and DIPEA (0.3 mL, 1.7 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(3-hydroxycyclobutyl)benzamide 15 as a mixture of cis and trans isomer. LC/MS (ESI+): m/z 336 (M+H). 1H NMR (400 MHz, DMSO) δ 8.80-8.66 (m, 2H), 8.61 (d, J=7.8 Hz, 1H), 8.56-8.47 (m, 1H), 8.43 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.06 (d, J=32.4 Hz, 2H), 8.01-7.91 (m, 1H), 7.63 (t, J=7.8 Hz, 1H), 5.12 (d, J=5.4 Hz, 1H), 5.03 (d, J=5.3 Hz, 1H), 4.50 (d, J=6.5 Hz, 1H), 4.37 (s, 1H), 4.03-3.81 (m, 2H), 2.95-2.78 (m, 1H), 2.62 (ddd, J=12.7, 11.7, 8.9 Hz, 1H), 2.40-2.27 (m, 1H), 2.20 (ddd, J=12.4, 8.0, 4.5 Hz, 1H), 1.97 (ddd, J=17.3, 8.6, 2.8 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].I[CH3:22].O.CN(C)[CH:26]=[O:27]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:22])([CH3:12])[C:9]([O:27][CH3:26])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CI
Reactant: CN(C)C=O
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(C)(C)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 2-(2-fluoro-biphenyl-4-yl)-propionic acid (15.0 g) was dissolved in N,N-dimethylformamide (150 ml) and then sodium hydride (6.14 g, 60% oily) was added, after which the resulting mixture was stirred for one hour. Subsequently, iodomethane (9.5 ml) was added and the mixture was stirred for 12 hours. A small amount of water was added to the reaction mixture and the resulting mixture was then subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by a recrystallization method from hexane, to obtain methyl 2-(2-fluoro-biphenyl-4-yl)-2-methyl-propionate (14.2 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][N:23]3[CH2:24][CH2:25][CH:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:27][CH2:28]3)[CH2:18][CH2:17]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: c1cc(C2CCN(CC3CCNCC3)CC2)ccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC(CN2CCC(c3ccncc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
A solution of 4-trifluoromethylphenylsulphonyl chloride (394 mg) in methylene chloride (4 ml) was added dropwise over 15 minutes to a mixture of 1-(4-piperidinylmethyl)-4-(4-pyridyl)piperidine hydrochloride (550 mg) and triethylamine (1.07 ml) in dichloromethane (10 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 2% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-[1-(4-trifluoromethylphenylsulphonyl)-(4-piperidinylmethyl)]-4-(4-pyridyl)piperidine (395 mg): NMR (CDCl3): 1.30 (m, 2H), 1.45 (m, 1H), 1.80 (m, 6H), 2.00 (dt, 2H), 2.20 (d, 2H), 2.30 (dt, 2H), 2.40 (m, 1H), 2.90 (d, 2H), 3.80 (d, 2H), 7.10 (d, 2H), 7.80 (d, 2H), 8.50 (d, 2H); m/z 468 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([N:15]=[C:16]=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(C)=O>[N:1]1([C:16]([NH:15][C:7](=[O:14])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[S:17])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a 50-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of morpholine (1.00 g, 11.5 mmol, 1.00 equiv) in acetone (10 mL). TEA (1.74 g, 17.2 mmol, 1.50 equiv) was added to the reaction, and the resulting solution was stirred for 30 min at 25° C. Benzoyl isothiocyanate (1.87 g, 11.5 mmol, 2.00 equiv) was added dropwise to the reaction at 0° C. The resulting solution was stirred for 30 min at 0° C., then quenched with 20 mL of water. The mixture was extracted with 2×30 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10-1:3) as eluent to furnish 2.30 g (80%) of N-(morpholine-4-carbonothioyl)benzamide as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21].[ClH:22]>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:21][C:15]2[CH:16]=[CH:17][C:18]([Cl:22])=[CH:19][C:14]=2[Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: Cl
Solvent: c1ccncc1
Product: O=C(Oc1ccc(Cl)cc1Cl)c1ccc(C(=O)Oc2ccc(Cl)cc2Cl)cc1
Reaction time: 6 h

Procedure:
The nitrogen-purged apparatus described in Example 17A for the preparation of DCPSeb was charged with 300 ml of molecular sieves-dried pyridine and 20.3 g of terephthaloyl chloride (0.10 moles, MW=203.0, Aldrich, 97%), which gave a cloudy, yellow mixture. A solution of 32.6 g of 2,4-dichlorophenol (0.20 moles) in 100 ml of dry pyridine was dripped into the stirred mixture over 15 min, causing a 1.3° C. exotherm. The mixture thickened and turned white. It was stirred 6 h more and left unstirred overnight. The mixture was slightly acidified with 10% aq HCl, the crude product isolated from it by vacuum filtration, then rinsed twice with ethanol on the funnel and dried on the funnel to 62 g of slightly wet solid. The product gave a hazy solution in 1200 ml of hot THF, which was filtered hot. After 2 h, a first crop of recrystallized solid was isolated by vacuum filtration and rinsed with a minimum of THF. More solids appeared in the filtrate after concentration to 200 ml. A second crop was taken as above after crystallization. The 2 crops were dried on their respective filtration funnels and then overnight at room temperature in a vacuum oven with a slight nitrogen bleed. The combined weight, 27.1 g, was 60% of the theoretical 45.6 g. Elemental analysis is consistent with theory. Calcd. for C20H10O4Cl4 : C, 52.7; H, 2.2; Cl, 31.1. Found: C, 52.8; H. 2.2; Cl, 31.5.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([OH:22])[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:27]C([O-])(C)C.[K+].CI>C1COCC1>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]([CH3:27])[C:20](=[O:22])[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc2nc(O)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(sc(=O)n2C)c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To a solution of (S)-2-(7-bromo-2-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67B) (40 mg, 0.090 mmol) in THF (1 ml) was added KOtBu (0.14 ml, 0.135 mmol, 1M in THF) slowly at −78° C. After 15 min, MeI (8.5 ul, 0.135 mmol) was added at −78° C. and stirred at −78° C. for 15 min. Then the reaction was reacted at rt for 3 hs. The reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 67C (30 mg, 73%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:10]([CH2:22][C:23](=[O:32])[NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)[N:9]=1)=[O:7])(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23]([CH2:22][N:10]2[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][C:8]([C:6]([OH:7])=[O:5])=[N:9]2)=[O:32])=[N:26][CH:27]=1
Reactant: COCCOCCOCc1cc(C(=O)OC(C)(C)C)nn1CC(=O)Nc1ccc(Cl)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COCCOCCOCc1cc(C(=O)O)nn1CC(=O)Nc1ccc(Cl)cn1

Procedure:
To a solution of 400 mg 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-[2-(2-methoxy-ethoxy)-ethoxymethyl]-1H-pyrazole-3-carboxylic acid tert-butyl ester in 5 ml DCM, 15 ml TFA were added at RT. After 3 h 30 ml toluene were added and the solvents were removed under reduced pressure. The residue was then three times codistillied with toluene and subjected to the next reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][OH:11].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.O>C1C=CC=CC=1>[CH3:16][S:17]([O:11][CH2:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:12][CH2:13][CH2:14][CH3:15])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(CO)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CCCCC(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To 24.7 g (0.1 mole) of the 2-(2,4-dichlorophenyl)hexan-1-ol and 13.8 g (0.12 mole) of methane sulfonyl chloride in 200 ml of benzene at 10° is slowly added 14.2 g (0.14 mole) of triethylamine. When the addition is complete the reaction is stirred and allowed to come up to ambient temperature over 1/2 hour period. The reaction slurry is then heated to reflux for 1/2 hour, cooled and poured into water. The organic solution is washed with dilute HCl then with water and finally with dilute sodium bicarbonate solution. After drying over anhydrous MgSO4, the benzene is stripped off to give 31.8 g (98%) of the crude product. This material is identified by ir and nmr. The purity is determined by glc.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[Cl:23][C:17]([C:11]1([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(C2(C(=O)O)CCCCC2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C2(C(=O)Cl)CCCCC2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 1-[4-(methoxycarbonyl)phenyl]-cyclohexanecarboxylic acid (E14) (0.174 g, 0.66 mmol) in dry dichloromethane (4 ml) under argon atmosphere at ice bath temperature oxalyl chloride (0.648 g, 5.10 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at room temperature for 15 minutes and at 40° C. for one hour, then concentrated under reduced pressure to give crude title compound (0.187 g, ca. 100%). The crude product was immediately utilized in the next step of the synthesis without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][N:15]=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:35]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:42])[CH2:24][CH2:23]3)[C:17]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(C(=O)c4cccnc4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A24 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (16 mg, 0.037 mmol), triethylamine (50 μl), nicotinoyl chloride (10 mg, 0.046 mmol), DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 1.95 (m,2H), 2.14 (m,2H), 3.07 (s, 3H), 3.55 (m, 1H), 3.65 (m, 2H), 4.13 (m, 1H), 5.72 (m, 1H), 7.40 (m,1H), 7.79 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.41 (s, 1H), 8.70 (m, 2H), 10.20 (s, 1H). Exact mass calculated for C22H22N6O6S 498.13, found 499.3 (MH+).