Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]([Cl:29])([Cl:28])[CH2:23][O:24][C:25](Cl)=[O:26].[OH-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:21][C:22]([Cl:29])([Cl:28])[CH2:23][O:24][C:25]([N:11]1[C:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:20][CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:26]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(n(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)C1
Yield: 28 %

Procedure:
1,3,4,9-Tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester (7.68 g), 2,2,2-trichloroethylchloroformate (5.8 ml), sodium hydroxide (2.8 g) and tetrabutylammonium iodide (catalytic) in dichloromethane (100 ml) were stirred under nitrogen at room temperature for 5 h. The mixture was diluted with dichloromethane (100 ml), washed with water (150 ml) and brine (100 ml), then dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed (SiO2, 1% methanol in dichloromethane) to give the title compound (3.53 g, 28%) as a yellow foam.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].[CH3:15][S-:16].[Na+]>CCO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][S:16][CH3:15])=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: COc1ccc(CCBr)c([N+](=O)[O-])c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CCSC)c([N+](=O)[O-])c1
Temperature: 25.5 °C
Yield: 60.9 %

Procedure:
A suspension of 1-(2-bromoethyl)-4-methoxy-2-nitrobenzene (14.7 g, 0.06 mol) in EtOH (150 mL) is stirred at 25-26° C. under a nitrogen atmosphere. Sodium thiomethoxide (7.9 g, 0.1 mol) is added in one portion at 25-26° C. and the reaction mixture is heated to reflux for 12 h. The solvent is removed under reduced pressure and the brown residue is taken up in cold water (100 mL). The crude product is extracted with EtOAc (2×200 mL). The organic layer is washed with water and brine (200 mL, each), then dried over Na2SO4 and the solvent is removed under reduced pressure to afford a brown oil. The crude product is purified by column chromatography (60-120 mesh silica gel, eluent 2% EtaAc in petrol ether) to give 8.3 g (67%) of the title compound as light brown liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.47-7.45 (m, 2H), 7.20-724(m 1H,), 3.81 (s, 3H), 3.01-2.97 (m, 2H), 2.69-2.66 (m, 2H), 2.05 (s, 3H). LC/MS: (ES+) 227.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[C:15]2=[O:20])[C@H:10]([CH2:21][CH2:22][CH3:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([Cl:43])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CCO>[Cl:43][C:40]1[CH:41]=[C:42]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][N:34]=[C:33]2[NH:19][C@H:16]1[CH2:17][CH2:18][N:14]([C@H:11]2[CH2:12][CH2:13][C@@H:8]([NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][C@H:10]2[CH2:21][CH2:22][CH3:23])[C:15]1=[O:20]
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: Clc1ccc2ncnc(Cl)c2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(Cl)cc23)C1=O
Temperature: 80 °C

Procedure:
Examples 2r and 2s, Step 1: A solution of (1R,3R,4S)-{4-[(3S)-3-amino-2-oxo-pyrrolidin-1-yl]-3-propyl-cyclohexyl}-carbamic acid tert-butyl ester (0.66 mmol) in EtOH (8 mL) was charged with triethylamine (0.5 mL, 3.3 mmol) and 4,6-dichloroquinazoline (200 mg, 1.0 mmol) before being heated at 80° C. for 12 h. The reaction mixture was cooled and purified by flash chromatography to afford tert-butyl (1R,3R,4S)-4-((S)-3-(6-chloroquinazolin-4-ylamino)-2-oxopyrrolidin-1-yl)-3-propylcyclohexylcarbamate. MS found: (M+H)+=502.2.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([CH:34]=O)=[CH:28]3)[CH2:21][CH2:20][CH2:19][CH2:18]1.N1CCCCC1>C(O)C>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[CH:34][C:29]2[NH:30][C:31]3[C:27]([CH:28]=2)=[CH:26][C:25]([O:24][CH2:23][CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:33][CH:32]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(-c3ccccc3)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 60.7 %

Procedure:
A mixture of 5-phenyl-2-oxindole (23 mg, 0.11 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (29 mg, 0.11 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 30 mg (61%) of the title compound as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]=[N+:16]=[N-:17])[C@H:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)F)CCOC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([CH2:14][N:15]=[N+:16]=[N-:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN=[N+]=[N-])[C@H](O)C1
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(CN=[N+]=[N-])CC1

Procedure:
To a solution of cis (±)-4-azidomethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.95 mmol, 0.5 g) was added bis(2-methoxyethyl)aminosulfur trifluoride (2.34 mmol, 0.52 g) slowly and stirred for 12. The reaction mixture was diluted with DCM (10 mL), washed with aq. NaHCO3 solution, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl acetate:hexanes (2:8) to get 4-azidomethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:38]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([F:27])=[CH:29][CH:30]=2)=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][C:21]([F:25])([F:26])[CH:22]([F:23])[F:24])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(Cl)c(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(Cl)c(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-1-propanol (208 mg, 0.53 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (273 mg, 91%).
Reaction SMILES: [CH:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)([CH2:3][CH3:4])[CH3:2].O[CH2:16][NH:17][C:18](=[O:22])[CH:19]([Cl:21])[Cl:20]>>[CH:1]([C:5]1[C:14]2[C:9](=[C:10]([CH2:16][NH:17][C:18](=[O:22])[CH:19]([Cl:21])[Cl:20])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C(NCO)C(Cl)Cl
Reactant: CCC(C)c1nccc2ccccc12
Product: CCC(C)c1nccc2c(CNC(=O)C(Cl)Cl)cccc12

Procedure:
1-sec-Butylisoquinoline and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to afford 1-sec-butyl-5-dichloroacetylaminomethylisoquinoline. The product was reacted successively in the same way as in steps (c), (d), (e) and (f) of Example 18 to obtain 1-sec-butylisoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-sec-butylisoquinoline-5-acetic acid as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:25]C(=O)C)[CH:17]=[C:18]([N:20]5[CH:24]=[CH:23][CH:22]=[N:21]5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:25][S:34]([CH:31]5[CH2:33][CH2:32]5)(=[O:36])=[O:35])[CH:17]=[C:18]([N:20]5[CH:24]=[CH:23][CH:22]=[N:21]5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: CC(=O)Nc1cc(-n2cccn2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Reactant: O=S(=O)(Cl)C1CC1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-n3cccn3)c2)cn1

Procedure:
The compound was prepared from the compound of Example 114 using the procedures of Example 115 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, CD3OD): δ 8.54 (s, 1H), 8.37 (d, 1H), 8.02 (s, 1H), 7.93 (d, 1H), 7.88 (s, 1H), 7.82-7.8 (m, 3H), 7.72 (d, 1H), 7.65-7.62 (m, 1H), 7.53-7.52 (m, 1H), 6.6-6.59 (m, 1H), 3.95 (s, 3H), 2.81-2.78 (m, 1H), 1.18-1.15 (m, 2H), 1.09-1.04 (m, 2H); LC-MS (ESI): Calculated mass: 459.52; Observed mass: 460.1 [M+H]+ (rt: 0.58 min).
Reaction SMILES: CS([O:5][CH:6]([CH2:9][CH3:10])[C:7]#[N:8])(=O)=O.[CH3:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=1O.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O.C(OC)(C)(C)C>[CH3:11][C:12]1[C:17]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:15]=[CH:14][C:13]=1[O:5][CH:6]([CH2:9][CH3:10])[C:7]#[N:8]
Reactant: CCC(C#N)OS(C)(=O)=O
Reactant: Cc1c(O)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC#N
Product: CCC(C#N)Oc1cccc(C(F)(F)F)c1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(methanesulfonyloxy)-butyronitrile (449 mg, 2.75 mmol), 2-methyl-3-trifluoromethylphenol (440 mg, 2.5 mmol), potassium carbonate (432 mg, 3.13 mmol) and potassium iodide (42 mg, 0.25 mmol) in acetonitrile (20 ml) was stirred overnight at 80° C. The mixture was shaken between tBuOMe and water, washed with NaCl (aq. satd) and the ethereal phase dried with MgSO4 and evaporated. The crude product was chromatographed on silica with EtOAc and hexane to give 2-(2-methyl-3-trifluoromethyl-phenoxy)-butyronitrile. 1H-NMR (CDCl3) 1.20 t, 3H; 2.15 dt, 2H; 2.36 s, 3H; 4.75, t, 2H; 7.17, d, 1H; 7.28, t, 1H; 7.37 d, 1H.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[S:36][C:35]([S:37](Cl)(=[O:39])=[O:38])=[C:34]([CH3:41])[C:33]=2[CH:42]=1>C1COCC1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[S:36][C:35]([S:37]([N:12]3[CH2:13][CH2:14][N:9]([C:4]4[C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:10][C:11]3=[O:15])(=[O:39])=[O:38])=[C:34]([CH3:41])[C:33]=2[CH:42]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: O=C1CN(c2ncccc2C(F)(F)F)CCN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)N2CCN(c3ncccc3C(F)(F)F)CC2=O)sc2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 3.5 %

Procedure:
A solution of 4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-2-one (150 mg, 0.61 mmol) in anhydrous THF (2.0 mL) was cooled to −78° C., followed by drop-wise addition of LHMDS (0.92 mL, 0.92 mmol (1.0 Min THF)). The reaction was allowed to stir five minutes after which a solution of 5-chloro-3-methyl-2-benzothiophene sulfonyl chloride in anhydrous THF (221 mg, 0.79 mmol in 1 mL) was added drop-wise. The reaction mixture was allowed to stir at −78° C. for approximately two hours, after which it was judged complete by TLC. The reaction was quenched with excess H2O (10 mL), extracted into ethyl acetate (3×10 mL), and finally washed with aqueous NaHCO3 (2×10 mL). The organic layers were combined and dried over Na2SO4, decanted, and concentrated in vacuo. The resultant crude oil was purified via normal phase SiO2 column chromatography using a 5%-20% EA/Hex solvent gradient. The desired product, was isolated in >95% purity, 3.5% yield (10 mg).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:16])C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]4([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[CH2:44][CH2:43]4)=[O:40])[CH:35]=[C:30]3[C:29]=2[CH3:55])=[CH:24][CH:23]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]4([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[CH2:43][CH2:44]4)=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:55]=[O:16])=[CH:26][CH:27]=1
Reactant: Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Temperature: 76 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
AIBN (6.5 mg, 0.040 mmol) was added to a stirring solution of NBS (26 mg, 0.15 mmol) and 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (61 mg, 0.13 mmol) in CCl4 (20 ml). The mixture was heated to 76° C. and allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (18.5 mg, 0.158 mmol) and subjected to MW irradiation (150° C.) for 10 min. The mixture was diluted with EtOAc and washed with 10% NaHSO4 2× followed by H2O and Brine. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (34 mg, 0.071 mmol, 54% yield) consistent by LCMS. LC-MS retention time: 1.64 min; m/z (MH+): 477. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 mM, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([F:32])=[CH:27][CH:26]=2)=[O:22])=O)(C)(C)C.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][C:38]2[N:41]=[C:42](C([O-])=O)[S:43][C:37]=2[CH2:36]1.[Li+]>O1CCOCC1>[CH2:18]([O:17][C:15]([C@H:13]1[CH2:12][CH2:11][C@H:10]([NH:20][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([F:32])=[CH:27][CH:26]=3)=[O:22])[C@H:9]([NH:8][C:6]([C:42]2[S:43][C:37]3[CH2:36][N:35]([CH3:34])[CH2:40][CH2:39][C:38]=3[N:41]=2)=[O:5])[CH2:14]1)=[O:16])[CH3:19]
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1S,2R,4S)-N2-tert-Butoxycarbonyl-4-ethoxycarbonyl-N1-[(5-fluoroindol-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18]N=CC=2)[CH:13]=1)=[O:7].O=[C:27]1[C:32](C(O)=O)=CC(C2C=CC=CN=2)=N[NH:28]1.C(Cl)(=O)C(Cl)=O.ClC1C=C(Cl)C=CC=1CN>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:32]=[CH:27][N:28]=2)[CH:13]=1)=[O:7]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: O=C(O)c1cc(-c2ccccn2)n[nH]c1=O
Agent: NCc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccccn2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-2-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 1 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.21 cm3 of 2,4-dichlorobenzylamine and 0.22 cm3 of triethylamine, 0.22 g of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-2-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at a temperature above 260° C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[S:15][C:16]=1[Cl:17]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:18]([C:14]2[S:15][C:16]([Cl:17])=[C:12]([Br:11])[CH:13]=2)(=[O:20])=[O:19])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Product: CC(=O)c1sc(NS(=O)(=O)c2cc(Br)c(Cl)s2)nc1C

Procedure:
The title compound was prepared from 5-acety1-2-amino-4-methylthiazole (42 mg) and 4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (11.7 mg) with purity >90%: MS (pos) m/z 415.3, 417.3.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[O:17][C:16]([C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:19])=[N:15][N:14]=1.C(O)(=O)C.O1CCOCC1>O.C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[O:17][C:16]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:2]([NH2:3])=[O:1])[CH2:29][CH2:28]3)=[N:23][CH:22]=2)=[O:19])=[N:15][N:14]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NC(=O)N1CCN(c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cn2)CC1
Reaction time: 16 h
Yield: 81.2 %

Procedure:
Sodium cyanate 34 mg (0.52 mmol) was added to a mixture of 5-[(2-fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Intermediate 41, 100 mg, 0.26 mmol) and glacial acetic acid (0.2 mL) in 0.6 mL of water (0.6 mL) and THF (0.3 mL). The mixture was stirred for 16 h then sodium cyanate (34 mg), glacial acetic acid (0.2 mL), dioxan (0.5 mL) and water (0.2 mL) were added. The mixture was stirred for another 2 h then directly purified by reverse phase HPLC, eluting with a gradient of acetonitrile/water containing 0.2% TFA, to give the title compound (90 mg, 82%) as a solid; 1H NMR δ 11.02 (1H, s), 10.74 (1H, s), 8.50 (1H, s), 8.05-7.95 (2H, m), 7.35-7.20 (2H, m), 7.20-7.10 (1H, m), 6.90 (1H, d), 3.60-3.4 (8H, m); MS m/e MH+ 427.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:35]
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Reactant: COCC(=O)Cl
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)COC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A178) and methoxy-acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[C:18]([Br:23])[CH:17]=2)=[CH:8][C:7]=1[CH3:24]>C(O)C.[OH-].[Na+]>[Br:22][C:20]1[CH:21]=[C:16]([C:15]#[C:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:25])=[O:2])=[C:7]([CH3:24])[CH:8]=2)[CH:17]=[C:18]([Br:23])[CH:19]=1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(Br)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC#Cc2cc(Br)cc(Br)c2)ccc1OCC(=O)O

Procedure:
A solution of {4-[3-(3,5-dibromo-phenyl)-prop-2-ynyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (207 mg, 0.44 mmol) in ethanol (50 ml) and 1N NaOH (5 ml) was stirred at 75° C. for 30 min. The reaction mixture was evaporated and the residue dissolved in water (10 ml). Aqueous 1N HCl (5 ml) was added and the mixture was extracted with methylene chloride (3×10 ml). The combined organic phases were dried and evaporated to give the title compound in 187 mg (93%) yield.
Reaction SMILES: C([O:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C@H:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:22]([O:21][C:19]([C@@H:9]([NH:8][C@H:7]([C:6]([OH:25])=[O:5])[CH3:24])[CH2:10][S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:20])[CH3:23]
Reactant: CCCCCCCSC[C@H](N[C@@H](C)C(=O)OC(C)(C)C)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCSC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The β-isomer of N-[(R)-1-ethoxycarbonyl-2-heptylthioethyl]-alanine t-butyl ester (2.4 g) prepared above was dissolved in 10 ml of TFA and the solution was stirred at room temperature for 3 hours. The TFA was evaporated off under reduced pressure. The residue was poured into ice water and adjusted to a pH of 4 with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from methylene chloride-ether, giving the β-isomer of the title compound. Yield 1.8 g. M.p. 124° to 126° C.
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[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1.[CH3:21][NH:22][O:23][CH3:24]>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:20])[N:22]([O:23][CH3:24])[CH3:21])=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccc(Oc2ccc3ccccc3c2)cc1
Reactant: CNOC
Solvent: c1ccccc1
Product: CON(C)C(=O)Nc1ccc(Oc2ccc3ccccc3c2)cc1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
Thirteen grams of 4-(2-naphthyloxy)phenyl isocyanate were dissolved in 100 ml of benzene, and a solution of 4 g of N,O-dimethylhydroxylamine in 50 ml of benzene was added dropwise thereto at a temperature below 30° C. The reaction mixture was allowed to stand at room temperature for 30 minutes, and the solvent was then removed under reduced pressure. The residue was recrystallized from ethanol to obtain 14 g of N'-[4-(2-naphthyloxy)phenyl]-N-methoxy-N-methylurea as white needles. M.P., 102°-103° C.