Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.C1C(=O)N([Br:33])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:33][CH2:25][C:9]1[C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1CBr
Yield: 85.2 %

Procedure:
19 g of methyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate is placed in 200 ml of CCl4 and 8.54 g of NBS and then 1 g of benzoyl peroxide are added, heating under reflux overnight. On returning to RT, the precipitate that forms is filtered and washed with CCl4. All of the filtrate is evaporated, then taken up in AcOEt and washed with saturated NaCl solution (twice). It is dried over MgSO4 and evaporated. The expected compound crystallizes in iso ether, it is filtered and dried to obtain 19.4 g of the expected compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH3:15])=[O:5])[CH3:2].[CH3:16]I.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:16])[C:7]=1[CH3:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice-water bath cooled solution of 2-methyl-1H-indole-3-carboxylic acid ethyl ester (5.197 g, prepared according to Suzuki et al. (1984) Synthesis (Stuttgart) 7:616-617), MeI (2.07 mL) in DMF (25 mL) was added NaH (1.33 g, 60% purity in mineral oil) under nitrogen gas stream. The reaction was stirred for 10 min at 0° C. and 20 min at room temperature and then quenched with diluted HCl solution, diluted with ice/water to a volume of ˜200 mL; the mixture was cooled with ice/water bath and the solids were collected with filtration, washed with water, and dried under high vacuum to give the desired crude product (5.87 g) as loose brown to yellow solid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.14-8.0 (m, 1H), 7.3-7.1 (m, 3H), 4.38 (q, 2H, J=7.1 Hz), 3.69 (s, 3H), 2.77 (s, 3H), 1.45 (t, 3H, J=7.1 Hz).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]([C:21]1[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[C:23]([CH3:35])[CH:22]=1)([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=1)[CH2:11][CH3:12])[CH3:9].[C:36]([C:38]1([OH:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)#[CH:37]>C(#N)C>[CH2:8]([C:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=1)([C:21]1[CH:26]=[CH:25][C:24]([C:37]#[C:36][C:38]2([OH:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:23]([CH3:35])[CH:22]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: C#CC1(O)CCCCC1
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCCC2)c(C)c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
Triethylamine (8.0 mL, 57.6 mmol), tetrakistriphenylphosphine palladium (2.2 g, 1.92 mmol) and cuprous iodide (0.36 g, 1.92 mmol) were added to a solution of trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester (Example 1-(1); 8.0 g, 19.2 mmol) and 1-ethynyl-cyclohexanol (3.5 g, 28.8 mmol) in acetonitrile (96 mL), and the mixture was stirred at 110° C. for 1.5 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (4.75 g, 63%).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([NH2:11])[CH3:10].C(N(CC)C(C)C)(C)C.[F:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:32]3[N:33]=[C:34]4[C:40]([C:41](O)=[O:42])=[CH:39][N:38]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:35]4=[N:36][CH:37]=3)=[N:27][N:28]2[CH3:31])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([NH:11][C:41]([C:40]1[C:34]2[C:35](=[N:36][CH:37]=[C:32]([C:26]3[C:25]4[C:29](=[CH:30][C:22]([F:21])=[CH:23][CH:24]=4)[N:28]([CH3:31])[N:27]=3)[N:33]=2)[N:38]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:39]=1)=[O:42])[CH3:10]
Reactant: C[C@@H](N)c1ccccn1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of (R)-1-pyridin-2-yl-ethylamine dihydrochloride (66 mg, 0.34 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.20 mL, 1.13 mmol), 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol), and HATU (95 mg, 0.25 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to give 117 mg (95%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)=[C:16]([F:27])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:26][C:23]1[CH:22]=[N:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[CH:15][C:16]=2[F:27])=[N:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3ncc(F)cn3)c(F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cnc(-c2ccc(C3=CCNCC3)cc2F)nc1

Procedure:
4-[3-Fluoro-4-(5-fluoro-pyrimidin-2-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (21AB) (717 mg, 1.92 mmol, 1 equiv) was treated with 10% solution of trifluoroacetic acid in dichloromethane at room temperature overnight.
Reaction SMILES: C([O:4][CH2:5][C:6]1([CH2:28][O:29]C(=O)C)[S:10][C:9]2[CH:11]=[C:12]3[S:16][C:15]([CH2:22][O:23]C(=O)C)([CH2:17][O:18]C(=O)C)[S:14][C:13]3=[CH:27][C:8]=2[S:7]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[OH:23][CH2:22][C:15]1([CH2:17][OH:18])[S:14][C:13]2[CH:27]=[C:8]3[S:7][C:6]([CH2:5][OH:4])([CH2:28][OH:29])[S:10][C:9]3=[CH:11][C:12]=2[S:16]1
Reactant: CC(=O)OCC1(COC(C)=O)Sc2cc3c(cc2S1)SC(COC(C)=O)(COC(C)=O)S3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCC1(CO)Sc2cc3c(cc2S1)SC(CO)(CO)S3

Procedure:
2,2,6,6-Tetra(acetoxymethyl)benzo[1,2-d:4,5-d']bis(1,3)dithiole (1.8 g, 3.5 mmol) and K2CO3 (1.9 g) were stirred in methanol (100 mL) for 1 h at ambient temperature. The solvent was evaporated and water (100 mL) was added. The mixture was neutralized (2M HCl) and the precipitate was collected. Yield: 1.20 g (99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:4].[F:23][C:24]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:25]=1[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:24]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:25]=1[CH2:26][N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16](=[O:18])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([S:8][CH2:7][C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:14][CH:13]=1
Reactant: CCCCCCCNCc1ccc(F)cc1F
Reactant: COC(=O)c1ccccc1CSc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)Cc1ccc(SCc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
(4-{[2-(Methoxycarbonyl)benzyl]thio}phenyl)acetic acid (581 mg, 1.836 mmol) and N-(2,4-difluorobenzyl)-N-heptylamine (465.3 mg, 1.968 mmol) were combined in DMF and the mixture was cooled in an ice-bath. HOBT (260.6 mg, 1.928 mmol) and TBTU (619 mg, 1.928 mmol) were added, followed by DIPEA (747.7 mg 5.785 mmol). The mixture was stirred at room temperature overnight and then evaporated. The resulting mixture was partitioned between ethyl acetate and sodium hydrogencarbonate aqueous solution (sat.). The aqueous portion was extracted with ethyl acetate and the combined organic extracts was dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 20 g/70 ml) using ethyl acetate/heptane (5:95, then 10:90) as eluant gave 767 mg the desired product, yield 77%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28](C)(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: N
Product: CC(C)(O)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 600 mg, 60%). mp 163–164° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.05 (s, 6H), 1.73 (t, J=6 Hz, 2H), 4.30 (s, 1H), 4.52 (t, J=6 Hz, 2H), 7.37 (t, J=9 Hz, 1H), 7.47 (s, 2H), 7.65 (dd, J=9 Hz, J=3 Hz, 2H), 8.83 (d, J=9 Hz, 2H), 8.95 (d, J=9 Hz, 2H), 8.18 (s, 1H); MS (DCI/NH3) m/z 448 (M+H)+. Anal. calcd. for C21H22FN3O5S: C, 56.36; H, 4.95; N, 9.39. Found: C, 55.96; H, 4.89; N, 9.09.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(N)ccc1OCc1ccccc1
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To 1-(Benzyloxy)-2-methoxy-4-nitrobenzene (26 g, 100 mmol) dissolved in ethanol (500 ml) in a 2 liter one-neck flask was added dropwise under 30 minutes a solution af sodium dithionite in water (500 ml), stirring was continued at ambient temperature for 2 h and after that the reaction mixture was heated at 70–80° C. for approx. 4 h, cooled and alkalized with sodium carbonate. The precipitate was filtered, washed with water and dried. The combined water phases were extracted with ethylacetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was combined with the filtered precipitate to afford 9.3 g (41% yield) of the product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:25]([CH:27]4[CH2:29][CH2:28]4)=[O:26])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([Cl:30])=[CH:10][C:9]=1[F:31])(C)(C)C>FC(F)(F)C(O)=O>[NH2:7][C:8]1[C:9]([F:31])=[CH:10][C:11]([Cl:30])=[C:12]([CH:13]=1)[O:14][C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][C:25]([CH:27]3[CH2:28][CH2:29]3)=[O:26])=[N:23][C:18]2=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A mixture of tert-butyl[4-chloro-5-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]carbamate (1.20 g, 2.51 mmol) and trifluoroacetic acid (10 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The solution was washed successively with saturated aqueous sodium hydrogen carbonate solution (50 mL×2) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (886 mg, 93%) as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18]C)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([OH:18])=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1N1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Yield: 93.5 %

Procedure:
To a 150 mL round-bottomed flask equipped with magnetic stirring was added methyl 2-[4-benzylpiperazinyl]benzoate (Preparation XIII) (2.3 g, 7.4 mmol) in THF (60 mL). A soln of LiOH (Aldrich) (940 mg, 22 mmol) in H2O (20 mL), was added and the reaction mixture was heated at 60° C. for 12 h. After cooling to RT, the reaction mixture was concentrated in vacuo and diluted with EtOAc (100 mL). A 10% soln of citric acid (25 mL) was added, the organic layer was separated and the aqueous layer was extracted with EtOAc (2×25 mL). The organic layers were combined, washed with H2O, satd NaCl, dried over Na2SO4, filtered and concentrated in vacuo to afford 2-[4-benzylpiperazinyl]benzoic acid as a white solid (2.05 g). MS (ESI, pos. ion) m/z: 297 (M+H). Calc'd for C18H20N2O2: 296.15: 296.15.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[O:10][CH3:11].Br[CH2:13][CH:14]([OH:16])[CH3:15]>>[NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:5][C:4]=1[O:10][CH3:11]
Reactant: CC(O)CBr
Reactant: COc1cc(O)ccc1CN
Product: COc1cc(OCC(C)O)ccc1CN

Procedure:
(rac)-1-(4-Aminomethyl-3-methoxy-phenoxy)-propan-2-ol is prepared starting from 4-aminomethyl-3-methoxy-phenol and (rac)-1-bromo-propan-2-ol in analogy to the procedures given in Example 18, steps a to c. LC-MS: tR=0.66 min, [M+1]+=212.13.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36]([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([O:39][CH3:36])[CH3:44])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)OC)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f28) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:11]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1ccccc1
Temperature: -10 °C
Yield: 84.9 %

Procedure:
A solution of 10.9 grams (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 14.1 grams (0.1 mole) benzoyl chloride in 200 milliliters xylene was refluxed at about 140° C. for 20 hours. Upon cooling the reaction mixture to -10° C., 13.7 grams (85% yield) pure product precipitated; m.p. 190.5° C.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[CH3:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.CN1CCCC1=O>O>[CH3:12][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][C:6](=[O:13])[NH:7]2)=[C:2]([N:18]2[CH:19]=[C:15]([CH3:14])[N:16]=[CH:17]2)[N:11]=1
Reactant: Cc1c[nH]cn1
Reactant: Cc1cc2[nH]c(=O)ccc2c(Br)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2nc(C)cc3[nH]c(=O)ccc23)cn1
Temperature: 140 °C
Reaction time: 20 h
Yield: 62.5 %

Procedure:
A mixture containing 9.56 g of 5-bromo-7-methyl-1,6-naphthyridin-2(1H)-one, 8.2 g of 4-methyl-1H-imidazole and 22 ml of N-methylpyrrolidin-one was heated with stirring in an oil bath at 140° C. for 20 hours. The reaction mixture containing some separated solid was diluted with about 150 ml of water and the solid was collected, triturated with water, washed with ethanol and dried to give 6.0 g of 7-methyl-5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 307°-308° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([N:22]([CH3:24])[CH3:23])=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:28]([Cu])#[N:29]>N1C=CC=CC=1>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([N:22]([CH3:24])[CH3:23])=[N:17][N:16]=[C:15]3[C:28]#[N:29])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1nnc(I)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: CN(C)c1nnc(C#N)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Temperature: 85 °C
Yield: 44.3 %

Procedure:
A mixture of 1-dimethylamino-4-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (40 mg, 0.082 mmol), pyridine (3 mL) and CuCN (22 mg, 0.247 mmol) was heated to 85° C. for 2 h and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired compound (14 mg, 44.2%) as a yellow solid. 1H-NMR (CDCl3) δ: 3.45 (s, 6H), 7.40-7.44 (m, 1H), 7.49 (t, 1H), 8.01 (d, 1H), 8.12 (s, 1H), 8.23 (d, 1H), 8.31 (s, 1H), 8.38 (d, 1H), 9.13 (s, 1H). m/z (M+1) 386.20.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH3:22][O:23][C:24]([C@@H:26]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:25].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH3:22][O:23][C:24]([C@@H:26]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[N:34]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:25]
Reactant: COC(=O)[C@@H]1CCCCCC[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCCCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.132 g, 0.396 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL). cis-2-(4-Fluoro-benzylamino)-cyclooctanecarboxylic acid methyl ester (0.117 g, 0.396 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.08 g, 0.416 mmol). Then N-methylmorpholine (0.84 g, 0.832 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, cis-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclooctanecarboxylic acid methyl ester (0.241 g, 0.396 mmol), as an orange oil. LC-MS (ESI) calcd for C27H33FN4O7S2 608.18, found 609.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15](O)=[O:16])(=[O:10])=[O:9])=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[N:36]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][CH2:38][CH2:37]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([NH:43][CH2:42][CH2:41][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:16])(=[O:10])=[O:9])=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:26]=2)(=[O:23])=[O:24])[CH:3]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cccc(CS(=O)(=O)c2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCC1)c1cccc(CS(=O)(=O)c2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 37.2 %

Procedure:
Following General Procedure R, the title compound (21 mg, 49%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic acid (48 mg, 0.085 mmol), 2-(pyrrolidin-1-yl)ethanamine (16 μl, 0.13 mmol), EDC (32 mg, 0.17 mmol) and DMAP (cat.) in DMF (2 ml).
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>C1(C)C=CC=CC=1>[C:1]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3ccccc23)nc1
Solvent: Cc1ccccc1
Product: Nc1ccc(Oc2cccc3ccccc23)nc1

Procedure:
To a solution of 13.11 g. (0.049 mol.) of 2-(1-naphthoxy)-5-nitropyridine in 250 ml. of toluene was added 1.31 g. of 5% paladium in carbon. The resulting mixture was placed in a 500 ml. Rocking Parr pressure vessel under 100 psig of hydrogen at r.t. for 3 hours. The mixture was filtered through celite and the filtrate was concentrated to give 11.5 g. (0.048 mol., 99.4%) of a yellow solid; mp. 82.2°-83.7°