Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([N:16]1[C:24]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:23][C:22]2[C:17]1=[N:18][C:19]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1)=[N:20][C:21]=2[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH:13]([CH3:15])[CH3:14]>CN1CCCC1=O>[C:8]([N:28]1[CH2:27][CH2:26][N:25]([C:24]2[N:16]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:17]3[C:22]([N:23]=2)=[C:21]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:20]=[C:19]([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)[N:18]=3)[CH2:30][CH2:29]1)(=[O:10])[CH3:9]
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: CC(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(C)C)CC1
Reaction time: 1 h
Yield: 61 %

Procedure:
Triethylamine (143 μl) and acetyl chloride (50 μl 0.72 mmol) were added to 5-(9-isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (2 ml of solution of 100 mg of this compound in 1 ml of N-methylpyrrolidone) and the resulting mixture was stirred for 1 hour. The resulting mixture was partitioned with ethyl acetate and water and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in methanol (2 ml) followed by the addition of 25% sodium methoxide-methanol solution (1 ml), and the resulting mixture was stirred for 3 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Dimethyl sulfoxide (3 ml) was added to the residue, then the resulting mixture was partitioned with ethyl acetate and water, the organic layer was similarly dried, and then the solvent was evaporated to give the title compound (150 mg, 61%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].ClC1C=CC(C2CC(=O)C(=CN(C)C)C(=O)C2)=CC=1>>[CH3:19][N:20]([CH:22]=[C:12]1[C:11](=[O:16])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][C:13]1=[O:15])[CH3:21]
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Reactant: COC(OC)N(C)C
Agent: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Product: COc1ccccc1C1CC(=O)C(=CN(C)C)C(=O)C1
Reaction time: 2 h

Procedure:
The title compound was prepared from 5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (386 mg, 1.77 mmol), example 1/a, and N,N-dimethylformamide dimethylacetal (2 ml), following the procedure described for 5-(4-chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (example 2/a stage 1) except that the reaction was run at 100° C. for 2 h, after which the solvent was removed by evaporation under reduced pressure to produce the title compound as a brown oil. The title compound was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:34]#[C:35][CH3:36])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CCOC(C)=O.N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28](/[CH:34]=[CH:35]\[CH3:36])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: C/C=C\[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 40 h
Yield: 98 %

Procedure:
To a stirred solution of 4.2 (0.055 g, 0.11 mmol) in EtOAc (4.00 mL, 41 mmol) at 23° C. was added quinoline (0.500 mL, 4.2 mmol) followed by Lindlar's Catalyst (0.012 g, 0.11 mmol). The reaction mixture was placed under an atmosphere of hydrogen and stirring was continued for 40 hours. The mixture was filtered through a pad of silica gel. The filtrate was washed with 1N HCl (3×10 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give compound 8.1 as a clear oil (0.0529 g, 96% yield). MS ESI (pos.) m/e: 513.3 (M+Na)+, 508.3 (M+H2O)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]([CH2:8][C:9]([CH3:11])=O)=O)=[O:5].[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][N:13]1[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:8][C:9]([CH3:11])=[N:14]1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: CNN
Solvent: CCO
Product: CCOC(=O)c1cc(C)nn1C
Yield: 43.1 %

Procedure:
Ethyl acetopyruvate (Organic Syntheses, Coll. Vol. I, 1944, p. 238) (31.6 g) was dissolved in ethanol (100 ml) and treated with methyl hydrazine (12 g) in portions. The mixture was then refluxed gently for 1 hr, whereupon most of the ethanol was removed in vacuo. The residue was poured into 5% NaCl solution and the product extracted with chloroform (3 × 100 ml). The combined extracts were washed with water, dried and the solvent evaporated. The residue was then distilled in vacuo. 1,3-dimethyl-5-ethoxycarbonylpyrazole (14.5 g 43%) was obtained as a colourless oil, b.p. 25 118-121° C. (A mixture of the two isomers (1.5 g), followed by pure 1,5-dimethyl-3-ethoxycarbonylpyrazole (10.5 g, 31%), b.p. 25 178-180° C, was obtained on continued distillation).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20](O)=[O:21])[C:15]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)=N[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]2[C:47](=[CH:48][CH:49]=1)[CH2:46][C:36]1([C:44]3[C:39](=[N:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]1=[O:45])[CH2:35]2.[CH:50]1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:30][C:25]1[CH:24]=[C:23]([C:15]2[N:16]([CH2:19][C:20](=[O:21])[NH:31][C:32]3[CH:33]=[C:34]4[C:47](=[CH:48][CH:49]=3)[CH2:46][C:36]3([C:44]5[C:39](=[N:40][CH:41]=[CH:42][CH:43]=5)[NH:38][C:37]3=[O:45])[CH2:35]4)[C:17](=[O:18])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:50]=2)[CH:28]=[C:27]([F:29])[CH:26]=1
Reactant: On1nnc2ccccc21
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)Cn1c(-c2cc(F)cc(F)c2)ncc(NC(=O)OCc2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cn1c(-c2cc(F)cc(F)c2)ccc(NC(=O)OCc2ccccc2)c1=O)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [5-{[(benzyloxy)carbonyl]amino}-2-(3,5-difluorophenyl)-6-oxopyrimidin-1(6H)-yl]acetic acid (91 mg, 0.22 mmol) [Veale et al. (1995) J. Med. Chem. 38, 98], 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (50 mg, 0.20 mmol) [Bell et al. WO 2006/031610], HOBT (34 mg, 0.22 mmol), and EDC (42 mg, 0.22 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[O:13][CH:12]([CH2:15][NH2:16])[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>O1CCCC1>[CH2:30]([O:29][C:27](=[O:28])[NH:16][CH2:15][CH:12]1[CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:14]=2[O:13]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCC1Cc2cccc(C3CCCC3)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCC1Cc2cccc(C3CCCC3)c2O1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
To a suspension of (7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.4 g, 9.46 mmol) in tetrahydrofuran (100 mL) cooled to 0° C. was added diisopropylethylamine (2.14 g, 16.58 mmol) followed by benzyl chloroformate (2.08 g, 12.19 mmol) and the reaction mixture was allowed to stir for 15 min. The reaction mixture was quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent removed in vacuo. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 2.52 g (76%) of (±)-benzyl(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a yellow oil. Rf=0.21 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C22H25NO3 C, 75.19; H, 7.17; N, 3.99. Found C, 74.74; H, 7.02; N, 3.85. Chiral HPLC separation of (±)-benzyl(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OJ, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=9.678 min, Chiralcel OJ, ethanol:hexane 1:1); Fraction 2 (Rt=12.824 min, Chiralcel OJ, ethanol:hexane 1:1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[CH3:38][S:39]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)(=[O:41])=[O:40]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 60.7 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), triethylamine (76 μL, 0.544 mmol), methanesulfonyl chloride (34 μL, 0.435 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 388, the title compound (108 mg, 61%) was obtained as a pale-green-powder.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14]C3C=CC=CC=3)[CH2:10][CH:9]2[C:21]([OH:23])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.ON1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2N=N1.Cl.[CH3:47][NH:48][O:49][CH3:50].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:10][CH:9]2[C:21]([N:48]([O:49][CH3:50])[CH3:47])=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNOC
Reactant: O=C(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.4 %

Procedure:
1,4-Bis(phenylmethyl)-2-piperazine carboxylic acid (5.0 g, 16 mmol) was dissolved in N,N-dimethylformamide (80 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.1 g, 16 mmol), 1-hydroxybenzotriazole (2.2 g, 16 mmol), N,O-dimethylhydroxylamine hydrochloride (1.9 g, 19 mmol) and triethylamine (2.7 mL, 19 mmol) were added thereto, and the mixture was stirred at room temperature for 3 days. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain the title compound (5.0 g, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[S:13]([OH:16])(=O)=[O:14].C(OCC)(=O)C.[CH2:23]([NH2:25])[CH3:24]>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[C:9]([S:13]([NH:25][CH2:23][CH3:24])(=[O:16])=[O:14])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1cccc(Cl)c1F
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cc(Cl)c(F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-chloro-2-fluorobenzoic acid (200 mg, 1.146 mmol) in chlorosulfonic acid (1.535 ml, 22.92 mmol) was stirred at room temperature for 30 seconds, then microwaved at 200 degrees for 10 rains. The reaction mixture was cooled to room temperature and dumped on ice (10 g) slowly. Ethyl acetate (25 ml) was added and extracted twice with ethyl acetate (10 mL X2). The combined organic phase was dried over MgSO4. Ethylamine (1833 μl, 3.67 mmol) in THF (2.0 M) was added, stirred at room temperature for 10 mins and washed with 1 N HCl (10 ml). The organic phase was dried over MgSO4 and concentrated to give the title compound, which was carried the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH2:16][CH:17]([F:19])[F:18])[N:3]=1>[Ni].C1COCC1.CO>[NH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]([O:15][CH2:16][CH:17]([F:19])[F:18])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)nc1OCC(F)F
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(N)nc1OCC(F)F

Procedure:
Prepared analogously to example 154d by hydrogenation of the product obtained in (803a) using Raney nickel in THF and methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[NH2:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OCc2ccccc2)c([N+](=O)[O-])cc1OC
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(N)c(OCc2ccccc2)cc1OC

Procedure:
To a hot suspension (60° C.) of 260 g 2-benzyloxy-4,5-dimethoxy-nitrobenzene in 900 ml of ethanol, 1350 ml of glacial acetic acid and 900 ml of water, 282.6 g of iron powder was added portion-wise over 30 min. Thereafter the mixture was refluxed for 1/4 h. The reaction mixture was poured into 10 l of water and the oily product was extracted with dichloromethane. After drying the solvent was evaporated. Yield: 116 g (50%). Melting point: 74° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:15]1[N:24]2[N:25]=[C:26]([NH2:28])[N:27]=[C:23]2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[N:24]2[N:25]=[C:26]([NH2:28])[N:27]=[C:23]2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccccc1)c1nc2ccccc2c2nc(N)nn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2c3ccccc3nc([C@H](N)c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a suspension of [(R)-(2-amino-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)-phenyl-methyl]-carbamic acid tert-butyl ester (0.05 g, 0.13 mmol), prepared as described in Example 49, in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 h, then the solvent was evaporated and the residue was diluted with ethyl acetate and washed with NaHCO3 satured solution then with water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to provide the title compound (0.02 g, 65% yield).
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH]Cl.[CH3:7][C:8]1[C:12]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([NH2:21])[NH:10][N:9]=1.[Na+].[Cl-:23]>C(Cl)Cl>[Cl:23][C:13]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:1][N:21]=[C:11]2[NH:10][N:9]=[C:8]([CH3:7])[C:12]=12
Reactant: [Cl-]
Reactant: O=N[O-]
Reactant: Cc1n[nH]c(N)c1C#Cc1ccccc1
Agent: [CH]Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
Sodium nitrite (2.3 g, 33.8 mmol) was added portionwise to cHCl (33 mL) at −15° C. and stirred for 15 min. 3-methyl-4-(phenylethynyl)-1H-pyrazol-5-amine (3.3 g, 16.9 mmol) was added as a solid, followed by the addition of CH2Cl2 (5 mL). The reaction mixture was allowed to warm up and stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 (28 mL) and NaCl (1.0 g) was added. The reaction mixture was heated to 50° C. for 16 h, then cooled to room temperature and partitioned between water and CH2Cl2. The organic layer was washed with water and brine, dried (phase separator cartridge) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, CH2Cl2, then CH2Cl2/ethyl acetate 9:1) yielding Compound Iu as a light yellow solid (1.9 g).
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([NH:14][C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3C(OC(C)(C)C)=O)[CH:19]=2)=[O:13])[CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:22]1[CH2:23][CH2:24][CH2:25][CH:21]1[CH2:20][N:18]1[CH:19]=[C:15]([NH:14][C:12]([C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:3]2[CH:2]=[C:1]([CH3:33])[CH:6]=[CH:5][CH:4]=2)=[O:13])[CH:16]=[N:17]1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CC3CCCN3C(=O)OC(C)(C)C)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CC3CCCN3)c2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of rac-tert-butyl 2-((4-(5-(m-tolyl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate (100 mg, 0.22 mmol) in DCM (2.3 mL), TFA (0.170 mL, 2.215 mmol) was added at 0° C. After stirring for 5 h at rt, the solvent and the remaining TFA was removed under reduced pressure. The residue was dissolved in DCM and 1 N aq. NaOH-solution was added until basic. The layers were separated and the aq. layer was extracted with DCM (1×). The combined organic layers were washed with brine, dired (MgSO4), filterd and the solvent was removed under reduced pressure to yield rac-N-(1-(pyrrolidin-2-ylmethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide a yellow oil which was used in the next step without further purification. LC-MS conditions A: tR=0.62 min, [M+H]+=352.07.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C1C(=O)N([Br:19])C(=O)C1.C(OCC)(=O)C.CCCCCC>CC#N>[NH2:1][C:2]1[C:7]([Br:19])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1c(O)cc([N+](=O)[O-])cc1Br
Reaction time: 1 h

Procedure:
A solution of 2-amino-5-nitrophenol (97, 24 g, 156 mmol) in CH3CN (1 L) was treated with NBS (28.8 g, 160.8 mmol) at room temperature. After stirring for 1 hour, the solvent was removed to afford brown precipitate, which was taken up with ethyl acetate:hexane (1:1). The precipitate was filtered and was used for the next step without further purification (33 g, 91%). A small amount of sample was purified by column chromatography on silica gel for analysis; 1H NMR (500 MHz, CD3OD): δ 4.93 (brs, 3H), 7.50 (d, 1H, J=2.4 Hz), 7.89 (d, 1H, J=2.4 Hz); 13C NMR (125 MHz, CD3OD): δ 105.5, 108.7, 121.8, 138.5, 143.7, 144.8; HRMS (FAB) calcd for C6H5BrN2O3 (M+) 231.9484, found 231.9479.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]([CH:22]([O:26][C:27](=[O:29])[CH3:28])[C:23](=O)[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([CH:22]([O:26][C:27](=[O:29])[CH3:28])[CH:23]([NH:14][C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)OC(Cc1ccccc1)C(C)=O
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: CC(=O)OC(Cc1ccccc1)C(C)Nc1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and acetic acid 1-benzyl-2-oxo-propyl ester.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:28]>CCCCCC>[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:20][CH2:19][C:6]3([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:31][CH:30]=1)[CH3:28]
Reactant: CCc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCC
Product: CCc1ccc(N2CCC3(CCNCC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 251 step A) from 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, dimethylaluminium chloride in hexane and 4-ethyl-phenylamine, with concomitant cleavage of the Boc protecting group under the conditions. MS (ESI): 259.1 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])[CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:23][CH:22]=1)#[N:20]>C(#N)C>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:49][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2/[CH:42]=[CH:41]/[CH:29]([CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)[CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1
Yield: 92 %

Procedure:
2.20 g (9.71 mmol) of 4-(tert-butyl)benzyl bromide and 2.02 g (14.59 mmol) of anhydrous potassium carbonate are added to a solution of 2 g (3.6 mmol) of methyl E4-[2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-enyl]benzoate in 8 ml of dry acetonitrile, and the mixture is heated under reflux for 12 hours. The mixture is then filtered and the filtrate is evaporated to dryness. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 1.9 g (3.30 mmol, 97% purity, 92% yield) of an oil are isolated.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH:10]([CH:13]([CH3:22])[CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH2:9][CH:8]=1)(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:35]1[CH:40]=[CH:39][C:38](N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=[CH:37][CH:36]=1.C1C[O:59][CH2:58]C1>>[CH:58]([C:38]1[CH:39]=[CH:40][C:35]([C:7]2[CH2:12][CH2:11][CH:10]([CH:13]([CH3:22])[CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH2:9][CH:8]=2)=[CH:36][CH:37]=1)=[O:59]
Reactant: CC(CNS(=O)(=O)C(C)C)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(CNS(=O)(=O)C(C)C)C1CC=C(c2ccc(C=O)cc2)CC1
Reaction time: 0.5 h
Yield: 26 %

Procedure:
N-[2-[4-[[(trifluoromethyl)sulfonyl]oxy]-3-cyclohexen-1-yl]propyl] 2-propanesulfonamide: To a −78° C. solution of 1.0 g (3.82 mmol) of the material prepared in Preparation 2 in 6 ml of THF was added 8.4 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF (8.4 mmol). The bath was removed and the mixture was stirred for 30 min and then 1.46 g (4.09 mmol) of N-phenyltrifluoromethane sulfonimide was added at ambient temperature. The mixture was stirred for 24 h. The reaction was quenched with NH4Cl saturated solution and extracted three times with ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (125 g of silica gel, 15% ethyl acetate/hexane) of the residue afforded 395 mg (26%) of the title compound.