Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1([C:5]2OC(=O)[S:7][N:6]=2)[CH2:4][CH2:3]1.[S:11]([C:21]#[N:22])([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].CCCCC>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1([C:5]2[N:22]=[C:21]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[S:7][N:6]=2)[CH2:4][CH2:3]1
Reactant: O=c1oc(C2(Cl)CC2)ns1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: Clc1ccccc1Cl
Solvent: CCCCC
Product: Cc1ccc(S(=O)(=O)c2nc(C3(Cl)CC3)ns2)cc1
Yield: 85.4 %

Procedure:
66.2 g (372 mmol) of 5-(1-chlorocyclopropyl)-1,3,4-oxathiazol-2-one and 70.9 g (391 mmol) of tosyl cyanide are stirred in 125 ml of 1,2-dichlorobenzene at 160° C. for 1 h. Subsequently, the reaction mixture is cooled and treated with pentane, and the precipitate is filtered off and dried under vacuum. 100.0 g of product are obtained (99.9% purity, 85.2% yield, log P (pH 2.3)=3.67).
Reaction SMILES: O[C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]=1
Reactant: CC1(O)CCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=CCCc2ccccc21
Yield: 139.6 %

Procedure:
A solution of 101.9 g (0.628 mol) of 1-hydroxy-1-methyl-1,2,3,4-tetrahydronaphthalene and 1.3 g of p-toluenesulphonic acid monohydrate in 1.3 liters of toluene was heated to reflux for 3 h with water being collected by means of a Dean Stark trap. The reaction mixture was cooled, washed with water (3×400 ml), then with saturated sodium chloride solution (400 ml), dried (K2CO3) and evaporated in vacuo to leave 126.4 g of brown liquid. This was vacuum distilled to yield 78.6 g (87%) of the title product as a pale yellow oil, b.p. 59°-62° C./1 mm of Hg. NMR δ(CDCl3) 2.06 (3H, m), 2.26 (2H, m), 2.76 (2H, t), 5.86 (1H, m), 7.11-7.27 (4H, m).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[N:24]=[C:23]([C:25](O)=[O:26])[O:22][N:21]=1>CC#N.CO>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:23]3[O:22][N:21]=[C:20]([CH3:19])[N:24]=3)=[O:26])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1noc(C(=O)O)n1
Solvent: CC#N
Solvent: CO
Product: Cc1noc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n1
Yield: 5 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (219 mg, 0.84 mmol) was coupled with 3-methyl-1,2,4-oxadiazole-5-carboxylic acid using the method of Example 34(d). Crude product was suspended in MeCN and MeOH. Suspension was filtered to give 16 mg (5%) the title compound as a colourless solid. Filtrate was purified by CombiFlash (column: C-18 silica, eluent: 0-100% MeCN in water). Fractions containing the title compound were combined and suspended in MeCN. Suspension was filtered to give 9 mg (3%) the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 2.44 (s, 3H), 4.34 (d, 2H), 4.39-4.53 (m, 1H), 6.95 (d, 1H), 7.84 (d, 1H), 7.92 (dd, 1H), 7.98 (d, 1H), 8.06 (d, 1H), 9.42 (d, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([OH:12])=[O:11])[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4](=[O:23])[CH2:3]1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCC.CCOC(C)=O>C1(C)C=CC=CC=1>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([O:12][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:11])[C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4](=[O:23])[CH2:3]1
Reactant: O=C(O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)OCc1ccccc1
Yield: 92 %

Procedure:
(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl)acetic acid (8.0 g, 25.78 mM) and benzyl alcohol (3.35 g, 31 mM) were dissolved in 200 ml of toluene and 0.5 g of p-toluenesulfonic acid were added and resulting mixture was refluxed until TLC (Hexane/AcOEt 8/12) showed completion of reaction. Organic layer was washed 3 times with sodium bicarbonate solution, dried and toluene evaporated providing 9.5 g of product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[I:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1cccc(F)c1
Solvent: CC#N
Product: O=c1c(I)c(OCc2ccccc2)ccn1Cc1cccc(F)c1
Temperature: 65 °C
Yield: 90.6 %

Procedure:
A mixture of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.83 g, 15.6 mmol) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) in anhydrous acetonitrile (55 mL) was heated at 65° C. for 4 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractions were collected according to ES MS (M+H 436) and washed with Na2SO3 to remove the color impurities. The fractions were concentrated under reduced pressure and dried in vacuo to afford the desired product (6.15 g, 90%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ7.73 (d, 1H, J=7.6 Hz), 7.36 (m, 6H), 7.08 (m, 3H), 6.39 (d, 1H, J=8.0 Hz), 5.28 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z 436.0196 (M+H calculated for C19H16NO2FI requires 436.0210).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15]1([C:20](Cl)=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:20]([C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[O:21])=[CH:24]1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=C(Cl)c1cccs1
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(c1cccs1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-thiophen-2-yl-methanone was prepared from phenanthridine, 2-thenoyl chloride, and indole according to GP 2. Yield, 17%. 1H-NMR (CD3OD): δ=6.17 (d, J=0.9 Hz, 1H), 6.67 (d, J=7.9 Hz, 1H), 6.84-6.89 (m, 2H), 6.91 (td, J=3.8 Hz, J=1.1 Hz, 1H), 7.02-7.11 (m, 2H), 7.18-7.24 (m, 2H), 7.26 (s, 1H), 7.38-7.46 (m, 2H), 7.50-7.56 (m, 2H), 7.93 (dd, J=7.9 Hz, J=1.3 Hz, 1H), 7.97-8.01 (m, 1H), 8.06 (d, J=7.9 Hz, 1H); (+)-ESI-MS: m/z=407 [M+H]+, 290 [M-indole+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][NH:44]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([N:44]3[CH2:45][CH2:46][CH2:47][CH2:48][O:43]3)=[O:29])[C:24]=2[CH:33]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: C1CCONC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)N4CCCCO4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and [1,2]oxazinane
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1>N1C=CC=CC=1>[C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1CCC[C@H](N)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CCC[C@H](NC(C)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
Acetic anhydride (1.20 ml, 12.7 mmol) was added to a solution of trans-methyl 3-aminocyclohexane-carboxylate (0.40 g, 2.54 mmol) in pyridine (10 ml) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The volatiles were removed in vacuum, the resulting residue was dissolved in DCM and washed with saturated sodium bicarbonate solution followed by brine solution (10 ml). After drying over anhydrous sodium sulfate and filtration the filtrate was concentrated under vacuum to afford 350 mg (69.0%) of trans-methyl 3-acetamidocyclohexanecarboxylate as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[CH2:30]2.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[N:31]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[CH2:30]2)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1Cl
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1Cl
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A mixture of 3-chloro-4-methylbenzoic acid (0.17 g, 1.0 mmol) and CDI (0.17 g, 1.1 mmol) was stirred in DMF (20 mL) at 40° C. under N2 for 4 hours. 3-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.31 g, 1.0 mmol) was added and stirring continued for 1 h at this temperature. Water (40 mL) was added and the resulting precipitate was filtered, washed with 4% aqueous HCl (40 mL) and dried in vacuo providing 3-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methyl-benzamide as a white solid (0.28 g, 65% yield); mp 229-231° C.; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min. 240 nm, 40/60 CH3CN/0.1% H3PO4. 4.29 (97.85%); 1H NMR (DMSO-d6) δ 1.97-2.01 (m, 1H), 2.32-2.45 (m, 4H), 2.57-2.62 (m, 1H), 2.85-2.96 (m, 1H), 4.31 (d, 1H, J=17.4), 4.45 (d, 1H, J=17.4), 4.58 (d, 2H, J=6.0), 5.11 (dd, 1H, J=13.2, J=5.1), 7.47-7.49 (m, 2H), 7.54 (s, 1H), 7.70 (d, 1H, J=7.8), 7.79 (dd, 1H, J=7.8, J=1.5), 7.95 (d, 1H, J=1.5), 9.21 (t, 1H, J=5.7), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 19.5, 22.5, 31.2, 42.8, 47.1, 51.6, 122.1, 122.9, 126.0, 127.1, 127.5, 130.4, 131.2, 133.3, 133.6, 138.9, 142.4, 143.7, 164.8, 167.9, 171.0, 172.9; LCMS: MH=426, 428; Anal. Calcd for C22H20ClN3O4+0.36 CH2Cl2: C, 58.84; H, 4.58; N, 9.21. Found: C, 58.49; H, 4.45; N, 8.91.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH3:28][NH:29][CH:30]1[CH2:32][CH2:31]1.C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH:30]1([N:29]([CH3:28])[C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:26])[CH2:32][CH2:31]1
Reactant: CNC1CC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1)C1CC1
Temperature: 70 °C
Reaction time: 22 h
Yield: 86.9 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (140 mg, 0.377 mmole), N-methyl cyclopropylamine (161 mg, 2.26 mmole), N-ethyldiisopropylamine (527 ul, 3.02 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 566 ul, 0.943 mmole) in tetrahydrofurane (5 ml) was stirred for 22 hours at 70° C. The solution is loaded on silicagel (1.5 g) and purified by chromatography on a 10 g Silicycle cartridge with ethyl acetate as eluent affording N4-cyclopropyl-N4,1-dimethyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (139 mg, 86.9%) as a white solid. mp.: 172-5° C., MS: m/z=415.4 (M+H+)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>CCO.O>[Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([CH:8]=[N:12][OH:13])=[N:6][CH:7]=1
Reactant: NO
Reactant: Cc1cc(C=O)ncc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C=NO)ncc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a solution of the compound obtained in Step B (3.1 g) in EtOH (47.5 ml) and water (23 ml) were added hydroxylamine hydrochloride (1.4 g) and sodium acetate (1.9 g). The reaction was stirred for 15 min at room temperature. The white solid was filtered off and the solution concentrated in vacuo to afford the crude title product (2.2 g, white solid), which was used directly for the next step. LCMS (Method F) 2.09 min, M+H 564/566.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH:27]5[CH2:29][CH2:28]5)[CH:25]=4)[N:20]([CH3:30])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH:27]5[CH2:29][CH2:28]5)[CH:25]=4)[N:20]([CH3:30])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C5CC5)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: COC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(C5CC5)cc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 38 %

Procedure:
In a 10 mL round-bottom flask, 2-(5-cyclopropyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (34 mg, 0.065 mmol) and TFA (0.5 ml, 6.5 mmol) were combined with dichloromethane (1.5 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1.5 mL) and ethylenediamine (0.11 ml, 1.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (dichloromethane/heptane) to afford 10 mg (38%) of 2-(5-cyclopropyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=405; 1H NMR (300 MHz, DMSO-d6) δ: 12.79 (br. s., 1H), 9.09 (s, 1H), 8.42 (s, 1H), 8.30 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.10 (dd, J=8.7, 1.5 Hz, 1H), 4.28-4.43 (m, 1H), 4.15 (s, 3H), 3.53 (dd, J=9.1, 4.5 Hz, 1H), 3.45 (dd, J=9.1, 4.9 Hz, 1H), 3.20 (s, 3H), 2.18-2.25 (m, 1H), 1.35 (d, J=6.8 Hz, 3H), 0.94-1.02 (m, 2H), 0.76 (td, J=5.3, 4.2 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([Br:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[Br-:27].[CH2:20]([N+:17]1[C:16]([CH3:18])=[C:15]([CH3:19])[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:10]=12)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc2c(OCc3ccccc3)cccn2c1C
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: Cc1c(C)[n+](Cc2ccccc2)c2c(OCc3ccccc3)cccn12
Product: [Br-]
Yield: 104.3 %

Procedure:
A solution of 2 g of 8-benzyloxy-2,3-dimethylimidazo-[1,2-a]pyridine at 50° C., dissolved in 40 ml of anhydrous acetone, is treated with 2.7 g of benzyl bromide and then heated under reflux for 16 h. The precipitate produced in this process is filtered- off and washed with cold acetone. 3.5 g of the title compound of m.p. 190°-192° C. are obtained.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.Cl.[N:48]1[CH:53]=[CH:52][C:51]([NH:54][NH2:55])=[CH:50][CH:49]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:51]3[CH:52]=[CH:53][N:48]=[CH:49][CH:50]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Reactant: NNc1ccncc1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccncc2)n1

Procedure:
1.10 g (2.40 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 656 mg (3.61 mmol) of 4-pyridylhydrazine dihydrochloride. After hydrolysis, 23 mg (2% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([CH2:17][Br:25])[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2nc(Cc3ccccc3)sc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2nc(Cc3ccccc3)sc2c1
Temperature: 25 °C
Yield: 25 %

Procedure:
Combine 2-benzyl-6-methyl-benzothiazole (0.6 g, 2.51 mmol), NBS (0.5 g, 2.63 mmol), AIBN (40 mg, 0.25 mmol), carbon tetrachloride (10 mL) and reflux for 3 h. Cool the reaction mixture to ambient temperature, dilute with chloroform and wash with water. Dry the combined organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the title compound as a white solid (0.2 g, 69%). MS (ES+) m/z: 319 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1([C:18]([C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)=[CH2:19])[CH2:17][O:16]1>CN(C=O)C>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]([OH:16])([C:18]([C:20]1[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=1)=[CH2:19])[CH2:17][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C=C(c1ccc(I)cc1)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(c1ccc(I)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 5 h
Yield: 59 %

Procedure:
Sodium 1,2,4-triazole (12.15 g, 133 mmol) was added to a solution of (2,4-difluorophenyl)-2-[1-(4-iodophenyl)ethenyl]oxirane [34.3 g, 89 mmol, from step (e)] in dry DMF (350 ml) under nitrogen at 70° C. The mixture was stirred for 5 hours, cooled, and the solvent removed under reduced pressure. The residue was partitioned between ether (800 ml) and water (2×500 ml). The organic solution was dried (MgSO4), filtered, and silica gel (60-200μ, 75 g) was added. The ether was removed under reduced pressure and the residual solid was applied to the top of a silica gel column (40-60%, 300 g) and the product was eluted using hexane and increasing amounts of ethyl acetate (0-75%). The product was obtained as a white foam (23.8 g, 61%), which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].C([Li])CCC.[Cl:15][CH:16]([C:19]1[O:24][C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([F:33])([F:32])[F:31])[C:21]=2[N:20]=1)[CH2:17][CH3:18]>O1CCCC1.CCCCCC>[Cl:15][CH:16]([CH2:17][CH3:18])[C:19]([NH:20][C:21]1[C:29]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](=[O:25])[CH2:8][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:9])=[O:24]
Reactant: CC(=O)Nc1nccs1
Reactant: CCC(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 21.7 %

Procedure:
Using the procedure of Step A of Example 6, a solution of 16.58 g of N-(2-thiazolyl)-acetamide in 340 ml of tetrahydrofuran, 155 ml of a solution of butyllithium in hexane and a solution of 17 g of the product of Step A in 170 ml of tetrahydrofuran were reacted to obtain 5.5 g of 2-[(2-chloro-1-oxo-butyl)-amino]-β-oxo-N-(2-thiazolyl)-3-trifloromethyl-benzenepropanamide melting at 170° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)=[O:36]>O1CCCC1>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:4](=[O:5])[C:3]([OH:7])([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:39][CH:38]=1)=[O:36]
Reactant: Nc1ccc(C(=O)c2ccccn2)cc1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccn1
Temperature: 43 °C
Reaction time: 0.25 h
Yield: 18.5 %

Procedure:
Tetrahydrofuran (15 ml, dry) was added to a mixture of 2,2-bis-trifluoromethyl-2-hydroxyacetic acid (1.08 g, 5.1 mmol) and 1,1'-carbonyldiimidazole (0.83 g, 5.1 mmol) while under a nitrogen atmosphere. There was an immediate evolution of carbon dioxide. The reaction was placed in an ultrasound bath at 23° C. for 15 min. The reaction was treated with 4-(2-pyridylcarbonyl)benzeneamine (1.01 g, 5.1 mmol), and heated to 43° C. in an ultrasound bath for 48 hr. The incomplete reaction was treated with a solid mixture of 2,2-bis-tri-fluoromethyl-2-hydroxyacetic acid (0.22 g, 1.04 mmol) and 1,1'-carbonyldiimidazole (0.20 g, 1.2 mmol) and heated to 53° C. in an ultrasound bath for 72 hr. The reaction was evaporated to a gold oil, which was treated with water (100 ml) and extracted with ethyl acetate (2×100 ml). the combined organic portions were dried (MgSO4) and evaporated to a gold oil. Chromatography of this oil on silica gel eluting with methylenechloride/ethyl acetate (first 100:0 and then 85:15) provided a tan solid (0.37 g, 19%); mp 197°-200° C. 1 H-NMR (250 MHz, d6 -DMSO): 7.68 (m, 1H, ArH), 8.00 (m, 6H, ArH), 8.74 (d, J=4.33, 1H, ArH), 9.93 (br s, 1H, OH), 10.83 (br s, 1H, NH). MS(CI,CH4): 393 (M+1).