Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8](C(OC(C)(C)C)=O)[N:7]=1)[CH3:3].[F:22][C:23]([F:35])([F:34])[S:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:3][CH:2]([N:4]([CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)[C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:23]([F:34])([F:22])[F:35])=[CH:26][CH:27]=1)=[O:33])[CH3:1]
Reactant: CC(C)NCc1nn(C(=O)OC(C)(C)C)c2ncccc12
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(Cc1n[nH]c2ncccc12)C(=O)Nc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To crude tert-butyl 3-[(propan-2-ylamino)methyl]-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (75 mg, 0.26 mmol) in 2 mL CH2Cl2 was added 4-(trifluoromethylthio) phenylisocyanate (57 mg, 0.26 mmol). The reaction was allowed to stir at ambient temperature for 16 h. To the reaction solution was added trifluoroacetic acid (1.0 mL, 1.35 mmol). The solution was allowed to stir at ambient temperature for 1 h, concentrated, and purified on a Gilson reverse phase preparatory instrument. The aqueous fractions were partitioned between saturated Na2CO3 and ethylacetate. The organics were washed with water and brine, dried over Na2CO3, filtered, and purified by silica gel chromatography to give 1-(1-methylethyl)-1-(1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-3-{4-[(trifluoromethyl)sulfanyl]phenyl}urea. 1H NMR (400 MHz, CDCl3): δ 11.69 (s, 1 H); 8.62 (dd, J=4.6, 1.5 Hz, 1 H); 8.54 (s, 1 H); 8.22 (dd, J=8.1, 1.5 Hz, 1 H); 7.51 (d, J=3.1 Hz, 4H); 7.24-7.21 (m, 1 H); 4.71 (s, 2 H); 4.61-4.51 (m, 1 H); 1.24 (d, J=6.8 Hz, 6 H. LCMS [M+H]+=410.1.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([CH2:12][NH2:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([CH2:12][NH:13][CH2:3][CH2:2][C:1]#[N:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCc1ccccc1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCNCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.3 g of acrylonitrile are added dropwise to a solution of 12.1 g of N-benzylmethylamine in 20 ml of ethanol. The reaction mixture is stirred for three hours at room temperature and then concentrated under vacuum to give 17 g (Y=97%) of the expected product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][C:20]#[CH:21].[Sn](Cl)(Cl)(Cl)Cl>>[C:1]([C:5]1[CH:10]=[C:9]([C:16](=[O:22])[CH2:17][CH2:18][CH2:19][C:20]#[CH:21])[CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCC(=O)Cl
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: C#CCCCC(=O)c1cc(C)c(O)c(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
To a solution of 2-tert-butyl-6-methylphenol (1.2 g, 7.3 mmol) in methylene chloride (28 ml, 1.1 equiv.), stirred under argon at -78° C., is added 5-hexynoyl chloride (1.0 g) followed by tin tetrachloride (0.93 mL, 1.1 equiv.). After stirring 30 minutes at -78° C., the reaction is warmed to -50° C. and stirred 5 minutes more. The mixture is then quenched with 1N HCl/ether. The product is extracted from 1N HCl with 3 portions of ether, and the ether layers are combined and washed with water. The resulting ether layer is dried (MgSO4), filtered, and concentrated in vacuo to give 2.14 g crude product. The product is flash chromatographed on silica gel using 10% EtOAc in hexane to give 0.97 g 2-t-butyl-4-(5-hexynoyl)-6-methylphenol. Crystallization from hexane gives crystals, mp 63°-64° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[C:7]1([C:5]2[N:6]=[C:2]([NH:1][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccccc2)cs1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)cs2)cc1

Procedure:
The title compound was prepared from 2-amino-4-phenylthiazole and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (29.8 mg) with purity >90%. MS (pos) m/z 359.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH2:21][CH3:22]>C(#N)C>[F:11][C:5]1[CH:4]=[C:3]([O:12][CH2:20][CH2:21][CH3:22])[C:2]([F:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9]
Reactant: CCCI
Reactant: O=[N+]([O-])c1cc(F)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 60 °C
Reaction time: 15 h
Yield: 46.9 %

Procedure:
To a solution of 2,5-difluoro-4-nitro-phenol (1.71 g, 9.77 mmol) in acetonitrile (20 mL), potassium carbonate (2.7 g, 19.5 mmol) and 1-iodopropane (1.14 mL, 11.7 mmol) were added. After stirring at 60° C. for 15 hours, mixture was concentrated and extracted with methylene chloride and 2M NaOH solution. Organic phases were dried over magnesium sulfate, filtered, and concentrated to give 1,4-difluoro-2-nitro-5-propoxy-benzene as a yellow solid (0.995 g, 47%). 1HNMR (CDCl3, 400 MHz) δ 7.92-7.88 (m, 1H), 6.83-6.78 (m, 1H), 4.08-4.05 (t, J=6.5 Hz, 2H), 1.95-1.86 (m, 2H), 1.10-1.06 (t, J=7.4 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.C([Li])CCC.CN(C)[CH:25]=[O:26].Cl>>[CH:25]([C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[O:26]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li]CCCC
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A 1 liter three neck round bottom flask equipped with equalizing addition funnel, magnetic stirer and temperature monitoring device was charged with N-(4-trifluromethylphenyl)-2,2-dimethyl propanamide (10.13 g, 41.4 mmol) and anhydrous tetrahydrafuran (150 mL). The reaction was chilled to -78° C. under nitrogen followed by slow addition of n-butyllithium (50 ml, 2.5 M in hexanes, 124 mmol) over 0.5 hours, such that the temperature of the reaction did not rise above -65° C. The contents were held at -78° C. for one hour, 0° C. for two hours, then chilled back to -78° C. Excess N,N-dimethylformamide (100 mL, 1.37 mol) was added. The contents were warmed to room temperature and stirred for two hours. Aqueous 1 N HCl was added to the reaction until the pH reached 1. The reaction was washed with water (2×200 mL), saturated ammonium chloride solution (2×200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The product was purified by flash chromatography (silica gel, 10% ethyl acetate, 90% hexanes) to yield, upon concentration of the appropriate fractions, N-(2-formyl-4-trifluoromethylphenyl)-2,2-dimethylpropanamide as a solid (7.36 g, 65%): mp 69-73° C. 1H NMR (CDCl3 /300 MHz) 11.5 (br s, 1H), 9.99 (s, 1H), 8.67 (d, 1H, J=8.8 Hz), 7.94 (d, 1H, J=1.6 Hz), 7.83 (m, 1H,), 1.37 (s, 9H). ESHRMS m/z 274.1060 (M+H, Calc'd 274.1055). Anal. Calc'd for C13H14F3NO2 : C, 57.14; H, 5.16; N, 5.13. Found: C, 57.15; H, 5.43; N, 5.01.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[O:17])[CH:25]=1)[CH3:19]
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Reactant: CCOC(=O)CCc1cccc(N)c1
Product: CCOC(=O)CCc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (131)(50 mg, 0.19 mmol) was coupled to aniline (124)(40 mg, 0.21 mmol) using Method D to give the product, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH:31]([S:39](Cl)(=[O:41])=[O:40])=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1(/[CH:32]=[CH:31]/[S:39]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: O=S(=O)(/C=C/c1ccccc1)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
N-[2-({[(E)-2-Phenylethenyl]sulfonyl}amino)-5-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and β-styrenesulfonylchloride (48 mg, 0.239 mmol according to general method 3 to give before Boc-deprotection 160 mg of a purple solid. MS (posES-FIA) m/z=Found: 499.2; Calcd 499.14; 1H-NMR δ 8.26 (d, 1H), 8.04 (d, 1H), 7.75–7.38 (m, 8H), 7.22 (d, 1H, J=15.4 Hz), 7.16 (d, 1H), 6.97 (d, 1H), J=15.4 Hz), 6.78 (dd, 1H), 6.68 (d, 1H), 3.68 (app t, 2H), 3.39 (app t, 2H), 3.28–3.21 (m, 4H).
Reaction SMILES: [N:1]1[N:2]([CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[N:1]1[N:2]([CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1nccs1
Reactant: CC(C)CC(C(=O)O)n1cc2ccccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)Nc1nccs1)n1cc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1 (640 mg, 2.76 mmol), 2-aminothiazole (284 mg, 2.76 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (1.0 g, 2.76 mmol) and 0.2 mL of Et3N in DMF (4 mL) was stirred at room temperature for 2 hours to provide the title compound, which was then purified by HPLC. 1H NMR (400 MHz, DMSO-d6) δ: 7.74 (d, J=12.0 Hz, 1H), 7.60 (d, J=12.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.25 (m, 2H), 7.05 (t, J=8.0, 8.0 Hz, 1H), 5.67 (m, 1H), 2.23 (m, 1H), 2.06 (m, 1H), 1.32 (m, 1H), 0.94 (d, J=8.0 Hz, 3H), 0.90 (d, J=8.0 Hz, 3H). [M+H] calc'd for C16H18OS, 314; found, 314.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-])=O)[C:5]=2[N:6]=1.CC(O)=O>CCOC(C)=O.[Fe]>[NH2:13][C:7]1[C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[C:10]([C:11]#[N:12])=[CH:9][CH:8]=1
Reactant: Cc1nc2c([N+](=O)[O-])ccc(C#N)c2o1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nc2c(N)ccc(C#N)c2o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
To a solution of 11B (0.16 g, 0.79 mmol) in EtOAc (2 mL) was added iron powder (0.1 g), followed by 10% aqueous AcOH (2 mL). The mixture was stirred at 60° C. for 2 h, then allowed to cool to rt and partitioned between saturated NaHCO3 and EtOAc. The separated EtOAc layer was concentrated under reduced pressure to give the title compound (0.14 g) as a solid.
Reaction SMILES: [Cl:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19](OC(C)(C)C)=O)[CH2:3]1.Cl.O1CCOCC1.BrC1[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:35][C:36]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:37]([CH3:39])[N:38]=2)[CH2:3]1
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](Cl)C2)nc1C
Yield: 40.4 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-3-chloro-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (198b) (101 mg, 0.258 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (71.0 mg, 0.284 mmol) and sodium carbonate (547 mg, 5.16 mmol), to obtain 48 mg of the title compound (40%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]=[C:18]([CH3:20])[CH3:19])=[C:15]([C:21]([OH:23])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[C:16]=2[CH:17]=[C:18]([CH3:20])[CH3:19])=[O:23])[CH2:29][CH2:27]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C=C(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C=C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 191.3 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(2-methylprop-1-en-1-yl)-1H-1,2,3-triazole-4-carboxylic acid (490 mg, 1.56 mmol) obtained in Example 95b), HOBt (106 mg, 0.779 mmol, 0.5 eq.) and cyclopropylamine (0.145 ml, 2.03 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 8.0 ml), WSC (366 mg, 1.87 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate-hexane (5:1, 48 ml) and washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane-THF (4:1:1, 48 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and ethyl acetate was added to the residue. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether and dried to give the title compound as a white powder (526 mg, 1.49 mmol, 95.4%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5](=[O:12])[CH2:6][C:7](OCC)=O)[CH3:2].[CH3:16][C:17]([CH3:21])=[CH:18]CCl.[O-]CC.[Na+].[OH-].[Na+]>>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:12])[CH2:6][CH2:7][CH:16]=[C:17]([CH3:21])[CH3:18])[CH3:15]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: CC(C)=CCCl
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCOC(OCC)C(=O)CCC=C(C)C
Yield: 57.2 %

Procedure:
Following the procedure stated in Referential example 1, reaction of 7.3 g of ethyl 4,4-diethoxyacetoacetate with 4.0 g of 3-methyl-2-butenyl chloride was carried out in the presence of sodium ethoxide and the resultant was decarboxylated with the alcoholic sodium hydroxide to yield 4.1 g of the desired product, b.p. 102°-103° C./1 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH2:17])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CO[C:20]1[CH2:21][CH2:22][CH2:23][N:24]=1>CO.C(O)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH:17][C:20]1[CH2:21][CH2:22][CH2:23][N:24]=1)[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC(Cc1cccnc1)c1cccc(Cl)c1Cl
Reactant: COC1=NCCC1
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(C(Cc2cccnc2)NC2=NCCC2)c1Cl
Temperature: 70 °C
Yield: 49.7 %

Procedure:
To 1-(2,3-dichlorophenyl)-2-(pyridin-3-yl)ethanamine (258 mg, 0.97 mmol) in methanol (5 mL) was added 5-methoxy-3,4-dihydro-2H-pyrrole (96 mg, 0.97 mmol) followed by acetic acid (2 drops). The mixture was heated at 70° C. for 16 hours. The mixture was cooled to room temperature and methanol was removed. Purification by chromatography on silica gel (5% 7N NH3 in MeOH/CH2Cl2) gave N-(1-(2,3-dichlorophenyl)-2-(pyridin-3-yl)ethyl)-3,4-dihydro-2H-pyrrol-5-amine (161 mg, 50%) as an off white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CI.[Li+].[CH3:24]C([N-]C(C)C)C>C1COCC1>[C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1([CH3:24])[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)C1c2ccccc2CN1C(=O)OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)c2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution N-BOC-1,3-dihydro-2H-isoindol-1-carboxylic acid, methyl ester (38 mmol) and MeI (10 mL, 160 mmol) in 150 mL of anhydrous THF at −30° C. was added LDA (Aldrich, 1.5 M in cyclohexane, 51 mL, 76.5 mmol). The reaction was allowed to warm up to rt over 4 h. The reaction was cooled to −30° C., and was quenched with saturated aqueous solution of NH4Cl (50 mL). The resulting mixture was partitioned between EtOAc and brine, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried with anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with 10:1 to 5:1 hexane/ether to afford N-BOC-1-methyl-1,3-dihydro-2H-isoindol-1-carboxylic acid, methyl ester.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](=[O:16])[NH:11][N:12]([CH3:15])[C:13](=[O:14])[C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18]1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH3:37][C:38]1[N:39]=[C:40]([CH2:48]Cl)[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2.O>CN(C)C=O>[CH2:1]([N:5]1[C:9]2[C:10](=[O:16])[N:11]([CH2:48][C:40]3[C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:47]=[C:38]([CH3:37])[N:39]=3)[N:12]([CH3:15])[C:13](=[O:14])[C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: Cc1cc2ccccc2c(CCl)n1
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(=O)n(C)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c(=O)n(C)n(Cc3nc(C)cc4ccccc34)c(=O)c21
Temperature: 50 °C
Reaction time: 5 h

Procedure:
0.20 g of (R)-1-(but-2-ynyl)-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-5-methyl-5,6-dihydro-1H-imidazo[4,5-d]pyridazine-4,7-dione and 0.10 g potassium carbonate are placed in 2 ml of dimethylformamide. Then 0.10 g of 3-methyl-isoquinolin-1-yl-methylchloride are added and the mixture is stirred for 5 h at 50° C. After the addition of water the mixture is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate, and the solvent is removed. The residue is purified over silica gel (cyclohexane/ethyl acetate 1:1).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:9]=[N:8][N:7]([CH3:10])[C:6]=1[C:11]([OH:13])=[O:12])=[O:4].N1(C(C2C=NN(C)C=2)=O)CC[CH2:16]1>>[N:2]1([C:3]([C:5]2[CH:9]=[N:8][N:7]([CH3:10])[C:6]=2[C:11]([OH:13])=[O:12])=[O:4])[CH2:14][CH2:16][CH2:1]1
Reactant: CN(C)C(=O)c1cnn(C)c1C(=O)O
Reactant: Cn1cc(C(=O)N2CCC2)cn1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)O

Procedure:
This compound was prepared in analogy to 4-dimethylcarbamoyl-2-methyl-2H-pyrazole-3-carboxylic acid (Example 97, step b) from azetidin-1-yl-(1-methyl-1H-pyrazol-4-yl)-methanone (500 mg, 3.33 mmol). Yield: 548 mg (81%); light red solid; MS: m/z=210.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[CH:23]=[CH:22][C:12]([CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C([O-])([O-])=O.[Na+].[Na+]>CCO>[OH:28][N:27]=[C:7]([C:6]1[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:23]=[CH:22][C:12]([CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1
Reactant: NO
Reactant: CCOP(=O)(Cc1ccc(C(=O)c2ccc(OC)cc2)cc1)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(C(=NO)c2ccc(OC)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Diethyl 4-(4-methoxybenzoyl)benzylphosphonate, 32-d, (500 mg, 1.38 mmol) was dissolved in 95% EtOH (5 ml). Hydroxylamine hydrochloride (288 mg, 4.14 mmol) and Na2CO3 (439 mg, 4.14 mmol) was added to the solution. The reaction mixture was then stirred for 10 h under reflux. The resulting mixture was cooled to ambient temperature, filtered. The filtrate was concentrated under reduce pressure, extracted with ethyl acetate/H2O (3×10 ml). The organic layer was combined and washed with brine (2×10 ml) dried over Na2SO4 anhydrous, concentrated under reduce pressure to dry. The pure product, 32-e, was obtained as colorless oil (460 mg, 88% yield). 1H NMR (300 MHz, CDCl3) δ 0.67-0.85 (m, 6H), 2.628-3.306 (m, 2H), 3.30-3.35 (d, J=46.8, 3H), 3.51-3.63 (m, 4H), 6.31-6.33 (m, 1H), 6.44-6.47 (m, 1H), 6.74-6.92 (m, 6H). LC-MS 378 [MH]+.
Reaction SMILES: [F:1][C:2]1([F:37])[CH2:3][CH2:4][N:5]([C:23]([C:25]2[S:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][C:26]=2[CH3:36])=[O:24])[C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2/[C:8]/1=[CH:9]/[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C>[F:37][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:23]([C:25]2[S:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][C:26]=2[CH3:36])=[O:24])[C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2/[C:8]/1=[CH:9]/[C:10]([NH:12][CH:13]1[CH2:14][CH2:15][N:16]([CH3:40])[CH2:17][CH2:18]1)=[O:11]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NC2CCNCC2)c2ccccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NC2CCN(C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
To a solution of 60 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]-N-(4-piperidyl)acetamide in 5 ml of dichloromethane were added 70 μl of a 40% aqueous solution of formaldehyde, 74 μl of acetic acid and 30 mg of sodium triacetoxy borohydride, followed by stirring at room temperature for six hours. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, followed by evaporating the solvent therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform) and crystallized from diethyl ether to give 53 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]-N-(1methyl-4-piperidyl)acetamide as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:5]2[C:10]3[N:11]=[C:12]([NH2:14])[S:13][C:9]=3[CH2:8][CH2:7][C:6]=12.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([NH:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][C:6]3=[C:2]([Cl:1])[S:3][C:4]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:5]3[C:10]=2[N:11]=1)(=[O:30])=[O:29]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CS(=O)(=O)c1sc(Cl)c2c1-c1nc(N)sc1CC2
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc2c(s1)CCc1c(Cl)sc(S(C)(=O)=O)c1-2

Procedure:
The title compound was prepared from 6-chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e][1,3]benzothiazol-2-amine (61 mg, synthesized according to METHOD I from 1-chloro-3-(methylsulfonyl)-4,5,6,7-tetrahydrobenzo-[c]thiophen-4-one) and 2,4-dichloro-6-methylbenzenesulfonyl chloride (54 mg) as described in the synthetic METHOD A to give a white solid (5.9 mg) with a purity >90%: MS-ES (pos) m/z 543.1.