Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:14]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]3([CH:26]=[CH:25][C:24](=[O:27])[CH:23]=[CH:22]3)[N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].ClC1C=CC(Cl)=CC=1Cl.[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>CC(C)=O>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]3[CH:26]=[CH:25][C:24](=[O:27])[CH:23]=[CH:22][C:12]3=[C:13]([S:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(C2=NC3(C=CC(=O)C=C3)C(Sc3ccccc3)=C2)CC1
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: C=CCN1CCN(c2cc(Sc3ccccc3)c3ccc(=O)ccn23)CC1
Yield: 41.6 %

Procedure:
By working as in Example 5, but starting with 2-(4-allyl-1-piperazinyl)-4-phenylthio-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (15.2 g) and 1,2,4-trichlorobenzene (150 cc), a residue is obtained which is redissolved in chlorofrom (300 cc). The solution obtained is poured into silica (300 g) contained in a column 4.2 cm in diameter. Elution is first performed with chloroform (1 liter) and this eluate is rejected. Elution is then performed with a mixture of chloroform and methanol (90:10 by volume) (3 liters) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in acetone (15 cc). Oxalic acid (1.9 g), dissolved in acetone (15 cc), is added to the solution obtained. The precipitate formed is separated by filtration and washed with ethyl ether (10 cc). 3-(4-Allyl-1-piperazinyl)-1-phenylthio-7H-pyrrolo[1,2-a]azepin-7 -one dioxalate (2.45 g), m.p. 225° C., is thereby obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8](SC)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[C:27]([CH3:36])[CH:26]=1>ClCCl>[Br:1][C:2]1[C:10]2[O:9][C:8]([NH:24][C:25]3[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[C:27]([CH3:36])[CH:26]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nc2cccc(Br)c2o1
Reactant: Cc1cc(N)ccc1C(=O)N(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Nc2nc3cccc(Br)c3o2)ccc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.49 g (2.01 mmol) 7-bromo-2-methylsulfanyl-benzooxazole in 30 ml dichloromethane, 3-chloroperbenzoic acid (0.494 g, 2.01 mmol) is added. This mixture is stirred for 1 h at room temperature. Then, 0.325 g (1.82 mmol) 4-amino-2,N,N-trimethyl-benzamide is added and the reaction mixture is heated to 40° C. with stirring continued for 20 h. The reaction mixture is concentrated in vacuo and the residue is purified by chromatography (silicagel, hexane:EtOAc=1:1=>1:4) to afford the title compound as an off-white crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:19]([O:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)[CH3:20].C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>>[CH2:19]([O:21][C:22](=[O:35])[C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:30][CH2:31][N:32]([C:2]3[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([I:16])[CH:10]=4)=[CH:4][N:3]=3)[CH2:33][CH2:34]2)=[CH:27][CH:28]=1)[CH3:20]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Nc1ccc(Cl)c(I)c1)c1ccc(Cl)nc1
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(Cl)c(I)c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(4-Chloro-3-iodo-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester was prepared from 6-chloro-N-(4-chloro-3-iodo-phenyl)-nicotinamide and 4-(piperazin-1-yl)-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester above. The product was isolated after suspension in small volume of EtOAc and filtration. HRMS m/z calcd for C25H24N4O3ClI [M+H]+: 591.0655. Found: 591.0655.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O-:12][Mn](=O)(=O)=O.[K+].[N:18](C(OCC)=O)=[C:19]=[O:20]>>[CH2:1]([N:8]1[C:9](=[O:12])[S:10][NH:18][C:19]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N=C=O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: S=C=NCc1ccccc1
Agent: Cl
Agent: [K+]
Product: O=c1[nH]sc(=O)n1Cc1ccccc1

Procedure:
Reagents: Benzyl isothiocyanate (0.81 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), ethyl isocyanatoformate (0.69 ml, 6.5 mmol).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:12])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)s1
Yield: 79.2 %

Procedure:
A solution of 5-bromothiophene-2-carboxylic acid (5.0 g, 24 mmol), methyl iodide (5.1 g, 30 mmol), and potassium carbonate (6.7 g, 48 mmol) in DMF (50 mL) was stirred at room temperature for 64 h. The reaction was quenched with water and the aqueous layer was extracted multiple times with ethyl acetate. The combined organic layers were washed with aqueous lithium chloride and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (4.2 g, 79%): 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J=4.0 Hz, 1H), 7.07 (d, J=4.0 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].CN1CCNCC1[Al+]C1CNCCN1C.CCOCC>O1CCCC1>[C:1]([NH:8][C:9]([CH3:14])([CH3:13])[CH2:10][OH:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN1CCNCC1[Al+]C1CNCCN1C
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(CO)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
N-Boc-aminoisobutyric acid is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over NaSO4 and evaporated to yield N-Boc-2-amino-2-methylpropanol.
Reaction SMILES: [CH2:1]([OH:16])[CH:2]([OH:15])[CH2:3][O:4][CH2:5][CH:6]([OH:14])[CH2:7][O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12].C(O)C(O)COCC(O)CO.[CH:28](=O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>[Pd]>[CH2:28]([O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8][CH2:7][CH:6]([OH:14])[CH2:5][O:4][CH2:3][CH:2]([OH:15])[CH2:1][OH:16])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: OCC(O)COCC(O)COCC(O)CO
Reactant: CCCCCCCCCC=O
Agent: [Pd]
Agent: OCC(O)COCC(O)CO
Product: CCCCCCCCCCOCC(O)COCC(O)COCC(O)CO
Yield: 15 %

Procedure:
The procedure of Example 1 is repeated, except 168.2 g (0.70 mol) of triglycerol from Solvay is used in place of diglycerol, 21.88 g (0.14 mol) of decanal is used in place of nonanal, and 1.1 g of 5% Pd/C is used in place of 1.03 g of 5% Pd/C. After the reaction completion, the product is extracted with diethyl ether (30 mL×7). The solvent is evaporated and a half of the crude product is chromatographed on silica gel using straight ethyl acetate. Appropriate fractions are combined, solvent evaporated to give 8.01 g of the product as a mixture of isomers. 1H NMR (δ, CDCl3, ppm): 0.88 t (3 H, CH3), 1.26 (14 H, (CH2)7), 1.58 t (2 H, CH2), 3.4-4.2 m (21 H, triglycerol moiety+CH2O+OH groups). 13C NMR (δ, CDCl3, ppm): 14.44, 23.02, 26.41, 29.64, 29.80, 29.90, 29.93, 32.20, 29.96, 64.15 (decyl), 69.82, 69.88, 71.04, 71.13, 71.99, 72.01, 72.03, 72.06, 73.24, 73.28, 73.32, 73.36 (triglycerol). GS/MS with TMS derivatization: 668 (MW+four TMS groups).
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[F:16][C:17]([F:25])([F:26])[C:18]1[CH:24]=[C:23]2[C:21](=[CH:20][CH:19]=1)[N:22]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 4-trifluoromethyl-aniline were reacted and treated with phenyl oxide to obtain ethyl 6-trifluoromethyl-4-hydroxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH2:33])[CH:28]=[CH:29][CH:30]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:21][O:20][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([CH3:15])([C:17](=[O:19])[NH:33][CH2:32][CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Reactant: NCCc1cccc(C(F)(F)F)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: COC(Cc1ccc(OC(C)(C)C(=O)NCCc2cccc(C(F)(F)F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(3-trifluoromethyl-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H26F3NO5 [M−H]−: 452.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17](=[O:29])[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[N:21]([CH3:27])[C:20]1=[O:28].O>CN(C)C=O>[CH2:1]([S:8][CH2:16][C:17](=[O:29])[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:25])([CH3:26])[N:21]([CH3:27])[C:20]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C(=O)N(CC(=O)CBr)C(=O)C1(C)C
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)N(CC(=O)CSCc2ccccc2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
Benzyl mercaptan (256 μl, 2.2 mmol) was stirred with cesium carbonate (712 mg, 2.2 mmol) in dimethyl formamide (5 ml) at room temperature for 1 hour. 3-(3-bromo-2-oxopropyl)-1,5,5-trimethylimidazolidine-2,4-dione (552 mg, 1.99 mmol) prepared as in WO99/06361 was added and the mixture stirred 18 hours at room temperature. The reaction mixture was treated with water, extracted into ethyl acetate (3×25 ml), the organic phases combined, brine washed and dried. The product was purified by silica chromatography, eluting with 50% ethyl acetate/iso-hexane to give 300 mg product.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:22])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2].[CH3:33][C:34](=O)[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:22])[CH2:21][N:20]([CH:34]([CH3:35])[CH3:33])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CNC3)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.7 %

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-azetidin-3-ol (100 mg, 0.23 mmol), propan-2-one (34 μL, 27 mg, 0.46 mmol) and 4 Å powdered molecular sieves (150 mg) in DCE (3 mL) was stirred for 3 h before sodium triacetoxyborohydride (96 mg, 0.46 mmol) was added. The resulting mixture was stirred for 16 h at r.t., then filtered through Celite®, washing with DCM. The filtrate was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 50-70%) affording 738 as a white solid (15 mg, 13%). LCMS (method I): RT 2.43 min, [M+H]+ 477.2. 1H NMR (MeOD, 400 MHz): δ 8.01-8.01 (1 H, m), 7.64-7.61 (1 H, m), 7.29-7.28 (2 H, m), 4.39 (5 H, s), 4.19-4.17 (2 H, m), 3.85 (4 H, s), 3.46 (2 H, d, J=8.87 Hz), 3.31-3.30 (5 H, m), 2.56-2.54 (1 H, m), 1.39 (3 H, t, J=7.50 Hz), 1.01 (6 H, d, J=6.25 Hz)
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]2[CH2:26][C@H:25]([OH:27])[CH2:24][C@@H:23]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][C:38]3=[O:43])=[CH:33][CH:32]=2)=[O:29])=[O:21])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]2[CH2:26][C:25](=[O:27])[CH2:24][C@@H:23]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][C:38]3=[O:43])=[CH:33][CH:32]=2)=[O:29])=[O:21])=[CH:15][CH:14]=1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1C(=O)Nc1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1C[C@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.1 %

Procedure:
0.21 g (0.98 mmol) of pyridinium chlorochromate (PCC) is added to the solution of 0.3 g (0.65 mmol) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(1R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide (Example 7) in 15 ml of methylene chloride, and the reaction mixture is stirred at room temperature for 48 hours. The precipitate is subsequently filtered off, and the filtrate is washed three times with 20 ml of water each time and dried over sodium sulfate. After the solvent has been stripped off, the residue is purified by preparative HPLC, giving 140 mg (47%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(R)-4-oxo-pyrrolidine-1,2-dicarboxamide as a white powder, ESI 457, m.p. 154°.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:26][CH2:27][CH2:28][CH3:29])[N:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:31]1.C(OCC)(=O)C>C1COCC1>[C:6]([C:5]1[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:10][C:2]([N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:31]2)=[N:3][C:4]=1[O:26][CH2:27][CH2:28][CH3:29])(=[O:7])[NH2:8]
Reactant: CCCOc1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCOc1nc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc(Nc2ccc(C(=O)N3CCOCC3)cc2)c1C(N)=O
Temperature: 100 °C
Yield: 76.2 %

Procedure:
A mixture of 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)-2-propoxynicotinamide (500 mg, 1.194 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (956 mg, 4.77 mmol) in THF (3 mL) was sealed in a vial and heated at 100° C. for 24 hrs. The reaction mixture was dissolved into ethyl acetate, washed with water, and concentrated. The solid material was chromatographed on an ISCO Companion 40 g silica gel column and eluted with (90:9:1 CH2Cl2:MeOH:NH4OH)/CH2Cl2 gradient (10-100%) to give 530 mg of (R)-tert-butyl 1-(5-carbamoyl-4-(4-(morpholine-4-carbonyl)phenylamino)-6-propoxypyridin-2-yl)piperidin-3-ylcarbamate as a white solid. LCMS: (M+H)+=583.46.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccccc3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 55 °C
Yield: 56.9 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216 mg, 2.59 mmol) in isopropanol (25 mL), 2-bromoacetophenone (780 mg, 3.87 mmol) was added. After heating the reaction mixture at 55° C. for 20 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (1.2 g) was chromatographed on silica gel with toluene/ethyl acetate (75/25) to give pure 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1H-imidazole (300 mg, 57%) as a white solid: mp (DSC) 202° C. Anal. Calc'd. for C22H17N2SO2Cl: C, 63.78, H, 4.28, N, 6.76, S, 7.74. Found: C, 63.69, H, 4.11, N, 6.68, S, 7.65. ##STR28##
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([O:11][C:12]1[CH:21]=[C:20]([O:22][CH:23]2[CH2:40][CH:39]3[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]4[C:36]([C:42]([OH:44])=[O:43])([NH:37][C:38]3=[O:41])[CH2:35]4)[CH2:24]2)C2C(=C(C)C(OC)=CC=2)N=1)[CH3:10]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:12]([O:11][CH2:9][CH3:10])[CH:21]=[C:20]2[O:22][CH:23]1[CH2:40][CH:39]2[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]3[C:36]([C:42]([OH:44])=[O:43])([NH:37][C:38]2=[O:41])[CH2:35]3)[CH2:24]1
Reactant: Nc1ccccc1Cl
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2cccc(Cl)c2n1

Procedure:
The title compound (10) was prepared from 2-chloroaniline following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (2): m/z=556 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:10]=1[O:11][CH2:12][C@@H:13]1[O:18][C@@H:17]([O:19][CH:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:21]Cl)[CH2:16][CH2:15][CH2:14]1.[I-].[Na+]>CN(C)C=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][CH:20]([O:19][C@H:17]2[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:12][O:11][C:10]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:9]=3[Cl:8])[O:18]2)[CH2:21][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:26][CH:27]=1
Reactant: c1c[nH]cn1
Reactant: ClCC(CCc1ccc(Cl)cc1)O[C@H]1CCC[C@H](COc2ccc(Cl)cc2Cl)O1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CCC(Cn2ccnc2)O[C@H]2CCC[C@H](COc3ccc(Cl)cc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.1 %

Procedure:
A solution of 90 mg of imidazole and 58 mg of 55% sodium hydride in 2 ml of dimethylformamide was stirred at 80° C. for 30 minutes and then left to cool to room temperature. 2 ml of a dimethylformamide solution containing 420 mg of trans-6-(2,4-dichlorophenoxymethyl)-2-[1-chloro-4-(4-chlorophenyl)-2-butoxy]tetrahydropyran and 132 mg of sodium iodide were then added to the mixture and stirring was continued at 90° C. for 4 hours. The mixture was then treated and the product purified essentially as described in Example 34(b)(i), to give 193 mg of the title compound as a colourless oil containing approximately B 1:1 mixture of isomers.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21](OC1C=CC=CC=1)=[O:22].[OH:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:21]([N:35]4[CH2:36][CH2:37][CH:32]([CH2:31][OH:30])[CH2:33][CH2:34]4)=[O:22])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: OCC1CCNCC1
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)N3CCC(CO)CC3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine, phenyl chloroformate and 4-hydroxymethyl-piperidine, the title compound was prepared as off-white powder. MS: m/e=422(M+H+).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]=2[CH:3]=1)=[CH:13][C:12]1[NH:17][C:18]2[CH:25]=[CH:24][C:23](C)=[CH:22][C:19]=2[C:20](=[O:21])[C:11]=1[CH:10]=3.N(CCO)(CCO)CCO>O>[CH:23]1[CH:22]=[C:19]2[C:20]([C:11]3[C:12]([NH:17][C:18]2=[CH:25][CH:24]=1)=[CH:13][C:14]1[C:15]([C:4]2[C:5]([NH:8][C:9]=1[CH:10]=3)=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:16])=[O:21]
Reactant: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Solvent: O
Solvent: OCCN(CCO)CCO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Reaction time: 7 h

Procedure:
20 g of C.I. pigment red 122 (in which the content of metal ions having a valence of at least 2 was 420 ppm), 60 g of the same aqueous dispersion of the pigment derivative (g″) as obtained in Comparative Example 27 and 60 g of deionized water were mixed, 10 g of 2% by weight triethanolamine was added, and the mixture was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 7 hours, to obtain a water-based pigment dispersion.
Reaction SMILES: [CH3:1][C:2]([S:22]([CH3:25])(=[O:24])=[O:23])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH:10]=[N:9]1)[C:3](O)=[O:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH:49]1[O:54][NH2:55]>CS(C)=O.CCOC(C)=O.O>[CH3:1][C:2]([S:22]([CH3:25])(=[O:24])=[O:23])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([B:13]2[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]2)[CH:10]=[N:9]1)[C:3]([NH:55][O:54][CH:49]1[CH2:50][CH2:51][CH2:52][CH2:53][O:48]1)=[O:4]
Reactant: CC1(C)OB(c2cnn(CCC(C)(C(=O)O)S(C)(=O)=O)c2)OC1(C)C
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)OB(c2cnn(CCC(C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To a solution of (2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoic acid (7.0 g, 0.019 mol) in DMSO (300 mL) was added HOBT (3.24 g, 0.024 mol). The reaction solution was stirred at room temperature for 20 min, EDCI.HCl (4.6 g, 0.024 mol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (2.5 g, 0.021 mol) were added at room temperature and the reaction mixture was stirred at room temperature overnight. Water (200 mL) and EtOAc (200 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL×3). The organic layers were combined and washed with H2O (50 mL), brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with MeOH/DCM (0-10% gradient) to give a 2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanamide (4.7 g, 52%). LC-MS M+H+472.2.