Azzindani/Open_Reaction_Data huggingface dataset:
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][N:23]1[C:27]([CH3:28])=[C:26]([S:29](Cl)(=[O:31])=[O:30])[C:25]([CH3:33])=[N:24]1>>[CH3:22][N:23]1[C:27]([CH3:28])=[C:26]([S:29]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)(=[O:30])=[O:31])[C:25]([CH3:33])=[N:24]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1nn(C)c(C)c1S(=O)(=O)Cl
Product: Cc1nn(C)c(C)c1S(=O)(=O)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 80 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and conditions outlined in procedure P. M.p.=273-275° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.88-7.85 (m, 1H), 7.64-7.58 (m, 1H), 7.56-7.52 (m, 1H), 7.32-7.29 (m, 1H), 3.72 (s, 3H), 3.50-3.44 (m, 2H), 3.09 (s, 2H), 2.71-2.65 (m, 2H), 2.38 (s, 3H), 2.22 (s, 3H), 2.11-2.05 (m, 2H), 1.91-1.82 (m, 2H); LCMS: 474 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.I[C:12]1[C:13]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)=[N:14][C:15]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:16][C:17]=1[O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:12]3[C:13]([NH:26][C@@H:27]4[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]4)=[N:14][C:15]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[N:16][C:17]=3[O:18][CH3:19])=[N:7][C:6]=2[CH:10]=1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I
Reactant: Clc1ccc2scnc2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(Cl)ccc2s1

Procedure:
Following the same procedure as in step 3 of Example 337 using 5-chloro-1,3-benzothiazole (59.4 mg, 0.35 mmol), tert-butyl (3R)-3-[[5-iodo-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (100 mg, 0.19 mmol), cesium carbonate (0.37 mg), tetrakis(triphenylphosphine)palladium (40.4 mg, 0.03 mmol, 0.18 equiv) and copper (I) iodide (6.7 mg, 0.04 mmol) in DMF (5.0 mL). The crude product was purified by chromatography on a silica gel column with ethyl acetate/petroleum ether (1:10-1:3) to afford the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=O.CN1CCOCC1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[S:16][CH:18]=[C:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: CCO
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(C(=O)O)cc3)cs2)CC1
Yield: 75.3 %

Procedure:
To a suspension of 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (13.3 mmol) in ethanol (60 ml) was added 4-(2-bromoacetyl)-benzoic acid (13.3 mmol) and 4-methylmorpholine (13.9 mmol). The reaction was heated at reflux for 2.5 h. The reaction was concentrated in vacuo and the solid washed with water (200 ml) to yield the title compound as a white solid (3.9 g). 1H NMR (400 MHz, CDCl3) 1.45 (9H, s), 3.58 (8H, m), 4.86 (1H, s), 6.95 (1H,s), 7.97 (2H, d, J 8 Hz), 8.1 (2H, d, J 8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:24][C:23]([CH3:33])([CH3:32])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.CO.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][C:23]([CH3:33])([CH3:32])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(CC(=O)O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 50 °C

Procedure:
To the product of Example 76 (46.5 mg, 0.127 mmol) was added KOH (10.3 mg, 0.184 mmol) in THF (1.5 mL), MeOH (0.2 mL) and water (0.075 mL). The reaction was heated to 50° C. After 27 min the reaction was cooled and diluted with EtOAc. The solution was washed with aq 2 M HCl and brine, dried (Na2SO4), filtered and concentrated to afford the product that was not purified further (LC-2) HPLC/MS: 476.0 (M+1), 478.0 (M+3); Rt=3.96 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([CH3:12])[N+:4]=1[O-])[CH3:2]>CC(O)=O.[Fe]>[CH2:1]([C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([CH3:12])[N:4]=1)[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])cc(C)[n+]1[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CCc1cc(N)cc(C)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-Ethyl-6-methyl-4-nitro-pyridine 1-oxide (27.65 g, 151.8 mmol) is dissolved in AcOH (330 mL) and Fe (powder, 33.9 g) is added. The mixture is stirred for 1 h at 100° C. The mixture is cooled to r.t. and filtered. The filtercake is thoroughly washed with AcOH and then discarded. The filtrate is evaporated, diluted with water (100 mL), basified (pH>10) with NaOH (1 M, 100 mL), filtered from the formed precipitate and the filtrate is extracted with CH2Cl2 (10×75 mL). The combined organic extracts are dried (MgSO4), filtered and evaporated to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C=O)C>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(CCCCC(=O)O)s2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc3c(s2)CCCCC3=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
Under nitrogen atmosphere, to a solution of 5-[5—(4-methylphenyl)thiophen-2-yl]valeric acid (2.60 g) in tetrahydrofuran (30 ml) was added oxalyl chloride,(1.24 ml) at room temperature and then a drop of DMF, and the mixture was stirred 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dichloromethane(30 ml). To the mixture was added tin tetra-chloride (1.5 ml) at 0° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane:=1:9→1:5) to give 2—(4-methylphenyl)-4-oxo-5,6,7,8-tetrahydro-4H-cyclo-hepta[b]thiophene (2.07 g) as pale yellow crystals.
Reaction SMILES: [ClH:1].COC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=C(N)C=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH3:55])=[CH:49][C:48]=3[N+:56]([O-])=O)[CH:42]=2)[O:37]1>>[ClH:1].[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH3:55])=[CH:49][C:48]=3[NH2:56])[CH:42]=2)[O:37]1
Reactant: CCOc1ccc(Oc2ccc3c(c2)CCC(c2cc(F)ccc2F)O3)c([N+](=O)[O-])c1
Agent: COc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c(N)c1
Agent: Cl
Product: CCOc1ccc(Oc2ccc3c(c2)CCC(c2cc(F)ccc2F)O3)c(N)c1

Procedure:
2-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-5-ethoxyphenylamine hydrochloride was prepared as described for 5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine hydrochloride in example 3(b) starting from 120 mg of 2-(2,5-difluorophenyl)-6-(4-ethoxy-2-nitrophenoxy)chroman. 1H NMR (400 MHz, CDCl3) δ: 7.26-7.22 (m, 2H), 7.01-6.74 (m, 7H), 5.22 (d, 1H, J 9.1 Hz), 3.90 (q, 2H, J 6.9 Hz), 2.90 (m, 1H), 2.68 (m, 1H), 2.19 (m, 1H), 1.90 (m, 1H), 1.34 (t, 3H, 6.9 Hz).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH2:36])[CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:49].Cl>>[ClH:1].[ClH:49].[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH:36][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCCC(CCN2CCCCC2)C1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CCN3CCCCC3)C2)c2ccccc21
Yield: 43 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[2-(piperidin-l-yl)ethyl]-piperidin-l-yl]ethanamine in a yield of 43% of theory. The dihydrochloride melted at 204°-208° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH2:13][CH:12]([C:14]3[O:18][N:17]=[C:16]([CH3:19])[N:15]=3)[CH2:11][N:10]=[CH:9]2)C=CC=CC=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[CH3:19][C:16]1[N:15]=[C:14]([CH:12]2[CH2:13][NH:8][CH:9]=[N:10][CH2:11]2)[O:18][N:17]=1
Reactant: Cc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C2CN=CNC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
1-Triphenylmethyl-1,4,5,6-tetrahydro-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidine (254 mg, 0.6 mmol) is dissolved in trifluoroacetic acid (TFA) (1 mL) with stirring at room temperature for 24 hours. The dark solution is then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 105 mg (62%) white crystals, mp 120°-122° C. identified by 300 MHz nmr. Calculated: C 38.57, H 3.96, N 19.99; found: C 38.72, H 4.09, N 19.78.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([CH3:16])[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].C([O-])(=[O:19])C.[K+].[OH-].[K+]>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:16][C@H:4]([CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:2][OH:19]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCl
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCO
Yield: 94 %

Procedure:
For the verification of the optical purity the compound obtained is hydrogenated on pre-hydrogenated platinum dioxide to (3R,7R)-1-chloro-3,7,11-trimethyldodecane; boiling point at 0.07 mm; 90°; αD =-1.2° (4.08% in CHCl3), which is converted by heating with dry potassium acetate in dimethylformamide (4 hours at 170°). This ester is purified by adsorption on silicagel (elution agent: n-hexane/ether 4+1), then further reacted to (3R,7R)-3,7,11-trimethyl-1-dodecanol by stirring with 4-N aqurous caustic potash (30 min. at room temperature). The mixture is extracted, washed neutral, dried, concentrated, distilled in the bulb-tube (115°, 0.20 Torr) and there is obtained (3R,7R)-3,7,11-trimethyl-1-dodecanol in 94% yield (based on (3R,7R)-1-chloro-3,7,11-trimethyldodecane employed). The product has an optical rotation value of [α]D20 =+3.7° (4.14% in n-octane) and is accordingly identical with authentic material.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C[OH:21].[OH-].[K+]>O>[OH:21][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: OCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(O)c1

Procedure:
2-(2-fluoro-4-biphenylyl)propionic acid (1 g.) ethylene glycol (10 ml.) and potassium hydroxide (0.8 g.) were refluxed under nitrogen for 24 hours. The mixture was diluted with water, washed with ether, acidified with hydrochloric acid and extracted with ether. The ether extract was washed with water, dried and evaporated to dryness. The product was subjected to thin layer chromatography to give 2-(2-hydroxy-4-biphenylyl)propionic acid, which was recrystallized from light petroleum (b.p. 80° - 100°C.) to give the purified acid having a m.p. of 112° - 119°C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:18][CH2:17][C:12]3([O:16]CCO3)[CH2:11][CH2:10]2)[C:6]([CH3:19])=[CH:5][C:3]=1[NH2:4].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[C:24]([Cl:34])=[CH:23][N:22]=1.Cl>CC(O)C>[Cl:34][C:24]1[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)=[N:26][C:21]([NH:4][C:3]2[C:2]([CH3:1])=[CH:8][C:7]([CH:9]3[CH2:10][CH2:11][C:12](=[O:16])[CH2:17][CH2:18]3)=[C:6]([CH3:19])[CH:5]=2)=[N:22][CH:23]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: Cc1cc(C2CCC3(CC2)OCCO3)c(C)cc1N
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 125 °C

Procedure:
A mixture of 2,5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline (86 mg, 0.33 mmol) and 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (104 mg, 0.43 mmol) in iPrOH (3 mL) was treated with HCl (82 μL, 4N in dioxane, 0.33 mmol) and heated to 125° C. in a sealed tube for 14 h. After cooling down to room temperature, the mixture was concentrated and was treated with acetone (2 mL) and HCl (330 μL, 4N in dioxane) at room temperature for 5 h. The mixture was then treated with saturated NaHCO3 aqueous solution (10 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined, concentrated and purified by flash column chromatography (silica gel, 0%-100% EtOAc in hexanes gradient) to provide 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)cyclohexanone as white solid; ESMS m/z 425.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[CH:14]([F:16])[F:15])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[F:15][CH:14]([F:16])[C:13]1[CH:12]=[C:11]([C:8]2[S:9][C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:7]=2)[N:30]([C:27]2[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=2)[N:31]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cccc2nc(C(=O)CC(=O)C(F)F)sc12
Agent: Cl
Product: Cc1cccc2nc(-c3cc(C(F)F)nn3-c3ccc(S(N)(=O)=O)cc3)sc12

Procedure:
The procedure of Example 9 was repeated using 1-(7-methylbenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[3-difluoromethyl-5-(7-methylbenzothiazol-2-yl)-1H-pyrazol-1-yl]benzenesulfonamide. NMR(DMSO-d6) δ: 2.54 (3H, s), 7.23 (1H, t, J=54.1 Hz), 7.34-7.57 (5H, m), 7.75-7.78 (3H, m), 7.94 (2H, d, J=8.6 Hz); mp 264-265° C. (ethyl acetate-ethanol)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](N)=[O:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[OH-:12].[Na+].Cl>>[NH2:1][C:2]1[C:3]([C:9]([OH:10])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: [OH-]
Reactant: NC(=O)c1ncc(Br)cc1N
Agent: Cl
Agent: [Na+]
Product: Nc1cc(Br)cnc1C(=O)O
Yield: 94 %

Procedure:
To a 100 mL round bottom flask, 3-amino-5-bromo-pyridine-2-carboxylic acid amide (1.05 g, 0.0049 mol) and aqueous sodium hydroxide solution (0.98 g in 10 mL water, 0.0245 mol) was added. The reaction mixture was stirred at reflux temperature for 5 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was neutralized to pH=7.0, using 2N HCl at 0° C. to obtain the precipitate. The precipitate was filtered and dried to get the title compound as light yellow solid [1 g, 95%]. 1H NMR (300 MHz, DMSO-d6): δ 7.65 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.01-7.16 (brs, 2H); LC-MS (ESI): Calculated mass: 215.9; Observed mass: 217.0 [M+H]+ (RT: 0.43 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:26]C=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[Cl-].[NH4+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:26])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cccc2oc(-c3ccc(Cl)cc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2oc(-c3ccc(Cl)cc3)nc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 7.3 %

Procedure:
2-(4-chlorophenyl)benzo[d]oxazole-4-carboxylic acid 4 (0.137 g, 0.5 mmol) in dimethyl formamide (10 mL) was added was added HOBT (0.085 g, 0.55 mmol), EDCI (0.115 g, 0.6 mmol), DIPEA (0.194 g, 1.5 mmol) and ammonium chloride (0.0265 g, 0.5 mmol). The reaction mixture was stirred at room temperature for 20 hr, cooled and poured into water (10 mL). The solution was acidified to pH=3 with 1N aqueous hydrochloric acid. Then the solution was extracted with dichloromethane (70 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, condensed in vacuum and separated by silica gel chromatography (ethyl acetate:methanol=1:0 to 10:1) to afford 10 mg 2-(4-chlorophenyl)benzo[d]oxazole-4-carboxamide (yield: 14.8%). 1H-NMR (400 MHz, DMSO-d6) δ 7.54-7.58 (t, J=8.0 Hz, 1H), 7.70-7.72 (d, J=8.0 Hz, 2H), 7.96-8.02 (m, 3H), 8.31-8.33 (d, J=8.0 Hz, 2H), 8.44 (s, 1H); LC-MS (ESI) m/z 273 [M+1]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[CH2:17])[C:12]([O:14]CC)=[O:13].[OH-].[Na+].[CH:20](Cl)([Cl:22])[Cl:21]>>[Cl:21][C:20]1([Cl:22])[CH2:17][C:11]1([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:12]([OH:14])=[O:13]
Reactant: C=C(C(=O)OCC)c1ccc2ccccc2c1
Reactant: ClC(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1(c2ccc3ccccc3c2)CC1(Cl)Cl
Reaction time: 2 h

Procedure:
Ethyl 2-(2-naphthyl)-acrylate (3.86 g) was dissolved in chloroform (4.3 g) tetraethylbenzyl ammonium chloride (36 mg) was added and sodium hydroxide (9 ml; 50%) added dropwise over 10 minutes at room temperature. The reaction mixture was stirred for an additional 2 hours and then quenched in ice water and extracted with ether. The solvent layer was washed sequentially with water, dilute hydrachloric acid and water again, and dried over anhydrous sodium sulphate. After evaporation of the solvents, the oily residue was chromatographed on silica gel using petroleum ether(b.p. 60°-80°) methylene chloride as eluent. The main fraction, a yellow oil (4.85 g), was distilled under vacuum to yield the ethyl ester of 2,2-dichloro 1-(2-naphthyl)cyclopropanecarboxylic acid identified by its i.r. and p.m.r. spectra. This ester was hydrolysed by refluxing in a 1 N sodium hydroxide/ethanol solution. On acidification thecyclopropane acid was obtained as a solid. This was recrystallised from petroleum ether (b.p. 40°-60°)/methylene chloride to yield (0.97 g; 31%) of the acid, m.p. 154°-5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-])=O)[C:5]=1[S:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([O-])=O.C([O-])(=O)C.[Na+]>CCO>[NH2:14][C:6]1[CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=[C:4]([NH2:1])[C:5]=1[S:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCSc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCSc1c(N)cc(C(C)(C)C)cc1N
Temperature: 78 °C
Reaction time: 0.58 h
Yield: 93 %

Procedure:
Dinitro compound 12 (20 mmol) and sodium acetate (200 mmol) were added to 50 ml EtOH. The mixture was heated to 78° C., and the solid dissolved completely. Stannous chloride dihydrate (200 mmol) was added to the solution, and the reaction mixture was stirred at 7° C. for 35 minutes. After removal of solvent under reduced pressure, the residue was dissolved in 800 ml EtOAc, and washed with 40% KCO3. The organic phase was dried, evaporated and the residue column chromatographed (SiO2) and eluted with a gradient of CH2Cl2/MeOH from 100:1 to 95:5 to produce 13 in 93% yield. 1H NMR. (500 MHz, CDCl3): δ 6.21 (s, 2H), 5.41 (s, 1H), 4.35 (br, 4H), 3.21 (t, 2H), 2.75 (t, 2H), 1.35 (s, 9H), 1.24 (s, 9H). ESI-MS: m/z: 340.5 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2cccc(Cl)c2)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2cccc(Cl)c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a solution of ethyl 2-[(3-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.051 g, 0.35 mmol) in ethanol (3.0 mL), piperidine (0.0035 mL, 0.035 mmol) was added at ambient temperature. The mixture was refluxed for 6 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound (0.061 g, y. 23%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:35][CH2:34][CH2:33][NH:32]2)[CH2:27][CH2:26]1>CN1C(=O)CCC1>[CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[N:15][C:2]([N:32]5[CH2:33][CH2:34][CH2:35][CH:31]5[CH:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: CN1CCC(C2CCCN2)CC1
Solvent: CN1CCCC1=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCCC3C3CCN(C)CC3)cc1OCC2
Temperature: 150 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
A mixture of 12-chloro-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene from Example 135 (160 mg, 0.480 mmol), TEA (0.50 mL), and 1-methyl-4-(pyrrolidin-2-yl)piperidine (161 mg, 0.960 mmol) in NMP (0.5 mL) was stirred at 150° C. for 24 h under nitrogen atmosphere. The resultant mixture was then purified by reverse phase combiflash eluting with a 0-50% gradient of CH3CN in 0.3% NH4HCO3 to give 106 (66 mg, 60% yield). LCMS (ESI): RT=4.11 min, m/z: 463.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6): δ 9.08 (t, J=10.5 Hz, 1H), 7.90 (t, J=10.5 Hz, 1H), 7.84 (t, J=10 Hz, 1H), 5.98 (t, J=20 Hz, 2H), 4.52-4.47 (m, 4H), 4.10 (s, 1H), 3.45 (d, J=6.5 Hz, 1H), 2.78 (s, 1H), 2.11 (d, J=10 Hz, 3H), 1.93-1.66 (m, 8H), 1.50-1.39 (m, 7H), 1.31-1.27 (m, 3H)