Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH2:14]([OH:17])[CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:16][CH2:15][CH2:14][OH:17])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(OCCO)c([N+](=O)[O-])c1
Yield: 74.5 %

Procedure:
20.25 g (0.1 mole) of 2,4-dinitrochlorobenzene, 124 g (2 moles) of ethylene glycol, 82.93 g (0.6 mole) of potassium carbonate, and 600 ml of xylene were placed in a reaction vessel to be stirred by heating for 12 hours. The reacted solution was isolated by filtration, and the filtrate was concentrated. 17.0 g of 2-(2,4-dinitrophenoxy) ethanol was yielded by column purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:9](SC)[S:8][CH2:7][C:6]=2[CH:13]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:9]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([Cl:14])[CH:16]=3)[S:8][CH2:7][C:6]=2[CH:13]=1
Reactant: CSC1=Nc2ccc(Cl)cc2CS1
Reactant: Nc1cccc(Cl)c1
Solvent: CCCCO
Product: Clc1cccc(NC2=Nc3ccc(Cl)cc3CS2)c1
Yield: 51.7 %

Procedure:
A mixture of 6-chloro-2-methylthio-4H-3,1-benzothiazine (69 g, 0.30 mole) and 3-chloroaniline (38.2 g, 0.30 mole) in n-butanol (250 ml) was refluxed overnight. After cooling in ice, the solid was collected by filtration and recrystallized from ethanol-water mixture to give 48 g (52%) of title product, m.p. 174°-175°.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[C:20](/[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[O:35][CH3:36])=[CH:24][CH:23]=2)\[CH3:21])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>>[Cl:34][C:32]1[CH:31]=[CH:30][C:29]([O:35][CH3:36])=[C:28]([C:25]2[CH:26]=[CH:27][C:22](/[C:20](/[CH3:21])=[CH:19]/[CH2:18][O:17][C:14]3[CH:15]=[CH:16][C:11]([CH2:10][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([OH:7])=[O:6])=[CH:12][CH:13]=3)=[CH:23][CH:24]=2)[CH:33]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)ccc3OC)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)ccc3OC)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (E)-(S)-ethyl 2-ethoxy-3-{4-[3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate (example 56) (0.47 g, 0.92 mmol) and sodium hydroxide (1M, 1.8 ml, 1.8 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid as a colourless gum, which contained 0.2 mol equivalents of ethyl acetate; 0.43 g (98%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[C:23](=[O:30])N(CCO)N=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[N:9]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: Cc1ccccc1NN
Product: COc1ccc(C2=NN(c3ccccc3C)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C (see starting compounds) and 2-methylphenylhydrazine as described for compound 35. Crystallization from methanol. M.p. 144°-145° C.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([OH:24])[C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:25])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:26][O:27][CH2:28]Cl>O1CCCC1>[O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([O:24][CH2:26][O:27][CH3:28])[C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:25])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COCCl
Reactant: CN1CCc2cc([N+](=O)[O-])c(O)cc2C(c2cccc3c2OCC3)C1
Solvent: C1CCOC1
Product: COCOc1cc2c(cc1[N+](=O)[O-])CCN(C)CC2c1cccc2c1OCC2
Reaction time: 22 h

Procedure:
(+)-5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (68.0 mg, 2.0 mmol) and potassium-tert-butylate (24.0 mg, 2.2 mmol) are dissolved in dry tetrahydrofuran (10 ml) at 23° C. Chloromethyl methyl ether (20.0 mg, 2.5 mmol) is added. The reaction mixture is stirred for 22 hours, filtered and the filtrate evaporated to dryness under reduced pressure. The resulting light yellow oil is purified using reverse phase HPLC (column 16 mm×250 mm, C18 7μ; eluent aceticnitril/0.1M ammoniumsulphate pH 3.3 (30:70), isocratic). The fractions containing the product are pooled. The pH is adjusted to 9.0, and the product extracted into dichloromethane. The organic phase is evaporated to dryness under reduced pressure.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][S:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(=[O:15])=[O:14]>>[NH2:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][S:13]([CH3:12])(=[O:14])=[O:15])=[CH:22][CH:21]=3)[N:7]2[N:8]=1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: Nc1nc2cccc(Br)n2n1
Product: CS(=O)(=O)Nc1ccc(-c2cccc3nc(N)nn23)cc1
Yield: 15.2 %

Procedure:
N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.80 g, 8.45 mmol) and 4-methylsulfonylaminophenyl boronic acid (2.0 g, 9.30 mmol), in a manner analogous to Step 73c. The residue was purified on a 40 g Isco silica gel column using a gradient of 0-15% methanol in dichloromethane as an eluent. N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide (389 mg, 15%) was isolated as a beige powder. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.06 (s, 1H), 7.96 (d, J=10.7 Hz, 2H), 7.49 (t, J=17.1 Hz, 7.5 Hz, 1H), 7.34 (d, J=8.6 Hz, 3H), 7.00 (d, J=7.5 Hz, 1H), 6.01 (s, 2H), 3.09 (s, 3H). MS=304 (MH)+. 84b) N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-phenyl]-methanesulfonamide (162 mg, 0.534 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (150 mg, 0.587 mmol) were combined in a manner analogous to Example 77 to yield N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl)-methanesulfonamide TFA salt (14 mg, 6%) as a yellow powder following purification via preparative HPLC on a Phenomenex Luna column using 0.1% TFA in MeCN and 0.1% TFA in Water as eluent. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.13 (s, 1H), 9.40 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.58 (m, 3H), 7.39 (d, J=7.5 Hz, 2H), 7.27 (d, J=8.6 Hz, 2H), 6.95 (d, J=9.6 Hz, 2H), 4.16 (m, 2H), 3.68 (m, 2H), 3.20 (m, 3H), 3.12 (s, 3H), 2.86 (m, 5H). MS=478 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.Cl[CH2:16][C:17]#[N:18]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][CH2:16][C:17]#[N:18]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: N#CCCl
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]cc(CCNCC#N)c2c1

Procedure:
Using the procedure of Step A of Example 25, 25 g of 5-methoxytryptamine, 10 ml of chloroacetonitrile and 37 ml of triethylamine were reacted to obtain 20.9 g of the expected product.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH:9]([O:11][CH2:12][CH3:13])=[CH2:10].[OH-].[Na+]>Cl.C1(C)C=CC=CC=1>[CH2:9]([O:11][CH:12]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH3:13])[CH3:10]
Reactant: C=COCC
Reactant: Oc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(C)Oc1ccccc1O

Procedure:
220 parts by weight of pyrocatechol is suspended in 200 parts by weight of toluene. After 2 drops of concentrated hydrochloric acid have been added 150 parts by weight of ethyl vinyl ether is dripped in while stirring. The internal temperature is prevented from rising above 65° C. by external cooling with ice. All of the pyrocatechol has dissolved upon completion of the reaction. 5 parts by weight of 2-normal caustic soda solution is added, the whole is allowed to cool, and dried over sodium sulfate, the solvent is removed and the product is distilled in vacuo. The yield is almost quantitative; boiling point 78° to 81° C. at 1 mm; nD25 = 1.5032
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:22][OH:23]>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH:21]([CH2:24][CH2:25][CH3:26])[CH2:22][OH:23])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: CCCC(N)CO
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Product: CCCC(CO)Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1

Procedure:
Prepared by the method of Example 231, using the product of Example 219 and 2-amino-1-pentanol.
Reaction SMILES: [CH:1]1([N:5]([CH3:17])[CH:6]2[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[CH2:4][CH2:3][CH2:2]1.[ClH:18].O1CCOCC1>C(Cl)Cl>[CH:1]1([N:5]([CH3:17])[CH:6]2[CH2:9][NH:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1.[ClH:18]
Reactant: CN(C1CCC1)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C1CCC1)C1CNC1
Temperature: 20 °C
Reaction time: 30 h

Procedure:
Combined a solution of tert-butyl 3-(cyclobutyl(methyl)amino)azetidine-1-carboxylate (285 mg, 1.186 mmol) in methylene chloride (6 mL) and added 4 M HCl in dioxane (1.186 mL, 4.74 mmol) and the solution stirred at 20° C. for 30 h. The solution was concentrated in vacuo and concentrated from heptane/methylene chloride to give the title compound as a hydrochloride acid salt (191 mg, 0.896 mmol, 76%) as a light yellow solid which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([Cl:19])=[N:16]3)=[CH:11][CH:10]=2)[C:4]1=[O:20].[CH3:21][O:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29]([S:33](Cl)(=[O:35])=[O:34])=[CH:30]2)=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:19][C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:33]([C:29]4[CH:28]=[CH:27][C:26]5[C:31](=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=5)[CH:30]=4)(=[O:35])=[O:34])[C:4]3=[O:20])=[CH:10][CH:11]=2)[N:16]=1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: N[C@H]1CCN(Cc2ccc3ccc(Cl)nc3c2)C1=O
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccc(Cl)nc5c4)C3=O)cc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline hydrochloride in place of 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J. The crude product is triturated in 20% EtOAc/hexanes and filtered to afford the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[ClH:17]>>[NH2:11][C:10]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][C:7]([Cl:17])=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: Cl
Product: Nc1cc(C(F)(F)F)c(Cl)nc1C(=O)O
Temperature: 150 °C
Reaction time: 1 h

Procedure:
3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate 3D) (100 mg, 0.334 mmol) was dissolved in 5M HCl (2.5 ml) and heated at 150° C., 5.5 bar in the microwave for 1 hour. The reaction mixture was purified by reverse phase chromatography eluting with water/MeCN to afford the title compound. MS m/z 241 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.33 (1H, br hump), 7.79 (1H, s), 7.19 (2H, br s
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]([N:11]2[C:16]3[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][C:13]([CH3:25])([CH3:24])[CH2:12]2)=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.C[Si](I)(C)C>C(Cl)(Cl)(Cl)Cl.O>[OH:2][C:3]1[C:8]([C:9]([N:11]2[C:16]3[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][C:13]([CH3:25])([CH3:24])[CH2:12]2)=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1C(=O)N1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC1(C)CN(C(=O)c2cccnc2O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 50 °C
Yield: 80.8 %

Procedure:
In 6 ml of carbon tetrachloride was dissolved 0.4 g of 3,4-dihydro-4-[(2-methoxypyridin-3-yl)carbonyl]-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine followed by dropwise addition of 0.26 g of trimethylsilyl iodide. The mixture was heated at 50° C. for 2 hours and, then, cooled. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure, and methanol was added to the concentrate for crystallization., Recrystallization from ethyl acetate gave 0.31 g of 3,4-dihydro-4-[(2-hydroxypyridin-3-yl)carbonyl]-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[S:4][CH:5]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)[N:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([N:10]2[CH2:11][CH2:12][O:13][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:14])([F:1])[F:15])[S:4][CH:5]=3)[CH2:9]2)[CH3:26])=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1nc(C2CNCCO2)cs1
Reactant: COc1ccc(CC(C)=O)cc1
Product: COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-(2-trifluoromethyl-thiazol-4-yl)morpholine with 4-methoxyphenyl-propan-2-one followed by purification of the base on a silica gel column using chloroform/ethyl acetate=9:1 as eluant.
Reaction SMILES: [CH3:1][N:2]1[C:10]([NH2:11])=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:3]1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[CH3:1][N:2]1[C:10]([NH:11][C:21]([NH:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[S:22])=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:3]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cn1nc2c(c1N)CCCC2
Solvent: CC(C)=O
Product: Cn1nc2c(c1NC(=S)NC(=O)c1ccccc1)CCCC2
Temperature: 60 °C

Procedure:
To a solution of compound 124 (5.44 g, 33.1 mmol) in 40 mL of acetone at 0° C. was added dropwise benzoyl isothiocynate (5.4 g, 33.1 mmol). The reaction mixture was gradually warmed up and stirred in an oil bath of 60° C. until TLC indicated there was no starting material remained.
Reaction SMILES: [OH:1][C@H:2]([C@H:6]1[C@@H:11]([NH:12][C:13](=[O:28])[CH2:14][NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:10][CH2:9][C@@H:8]([NH:29]C(=O)OC(C)(C)C)[CH2:7]1)[CH:3]([CH3:5])[CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C@@H:8]1[CH2:9][CH2:10][C@H:11]([NH:12][C:13](=[O:28])[CH2:14][NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C@H:6]([C@@H:2]([OH:1])[CH:3]([CH3:4])[CH3:5])[CH2:7]1
Reactant: CC(C)[C@H](O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](O)[C@@H]1C[C@H](N)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
The entirety of tert-butyl(1R,3R,4S)-3-((S)-1-hydroxy-2-methylpropyl)-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate prepared in previous Step (1 eq) in CH2Cl2 (20 mL) was added TFA (4 mL) at RT. The reaction was stirred for 5 h and concentrated in vacuo. The residue was partitioned between 1N NaOH (30 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the organic phases were combined, washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give N-(2-((1S,2R,4R)-4-amino-2-((S)-1-hydroxy-2-methylpropyl)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide. MS found: (M+H)+=416.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[C:13](=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:27])[N:6]=1)[CH2:3][CH3:4].Cl[C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[NH:35][CH:36]=[N:37][C:30]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:37]1[C:30]2[C:31](=[N:32][CH:33]=[CH:34][C:29]=2[NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:23])[F:24])[CH:16]=3)[C:13](=[O:26])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:27])[N:6]=2)[CH2:3][CH3:4])[NH:35][CH:36]=1
Reactant: Clc1ccnc2[nH]cnc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ccnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (38 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 7-chloro-3H-imidazo[4,5-b]pyridine (23 mg, 0.15 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[CH:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[C:8]([CH3:23])[C:6]=3[N:7]=2)=[CH:39][CH:40]=1
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3ccc(N)nc3)nc12
Yield: 99.2 %

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 50 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give 67.3 mg of 202. MS (Q1) 498.3 (M)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C(OCC)(=O)C.CO>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CCS(=O)(=O)Nc1cccc(C(C)=O)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Temperature: 150 °C
Yield: 56 %

Procedure:
2 g (8.8 mmol) of N-(3-acetyl-phenyl)-ethanesulfonamide were dissolved in 15 ml of N,N-dimethylformamide dimethyl acetal and heated at 150° C. for 12 h. The solvent was removed by reduced pressure distillation to yield a crude which was chromatographied (silica gel) using ethyl acetate/methanol as eluent. 1.4 g (yield=56%) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-ethanesulfonamide were obtained.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.[N:27]([CH2:30][CH2:31][O:32][CH3:33])=[C:28]=[O:29].C(N(CC)CC)C>C1COCC1>[CH3:33][O:32][CH2:31][CH2:30][NH:27][C:28]([N:14]1[CH2:15][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=2)[CH2:11][CH:12]([NH:16][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:24])[CH2:13]1)=[O:29]
Reactant: COCCN=C=O
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCNC(=O)N1CC(NC(=O)c2ccccc2)CC(c2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg (0.19 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 2.5 ml of THF, and 19 mg (0.19 mmol) of 1-isocyanato-2-methoxyethane and 29 μl (0.21 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 32 mg (35% of theory)
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[NH:22]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=[CH:23]1>>[N:22]1([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]([N:9]3[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]3)=[O:13])=[CH:15][CH:16]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1=CC=CNC=C1
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CCC(CC)N1CCN(C(=O)c2ccc(CN3CCCCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 12 and azepine.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][OH:22])[CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:24]1[CH:56]=[CH:55][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]2=[O:54])=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][O:22][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][CH:29]4[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]4=[O:54])=[CH:26][CH:25]=3)[CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(S(=O)(=O)c2ccccc2)cc1
Yield: 88.9 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 1.006 g of 2-[1-(4-phenylsulfonylphenyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 35), 1.40 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 866 mg of triphenylphosphine and 549 mg of diethyl azodicarboxylate, 2.05 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH:20]3[CH2:22][CH2:21]3)[C:16](=[O:19])[NH:17][N:18]=2)=[CH:10][CH:9]=1.Cl[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(#N)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:17]1[C:16](=[O:19])[N:15]([CH:20]2[CH2:22][CH2:21]2)[C:14]([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)=[N:18]1)[CH3:29]
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reaction time: 2 h

Procedure:
586 mg (4.24 mmol) of potassium carbonate are added to 500 mg (2.12 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 36A and 260 mg (2.12 mmol) of ethyl chloroacetate in 10 ml acetonitrile and the mixture is heated under reflux with stirring for 2 hours. It is then concentrated, the residue taken up in water is extracted with dichloromethane, the organic phase dried over sodium sulphate and again concentrated. After purification by flash chromatography over silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1) 448 mg (66% of theory) of the target compound are obtained.